• -zna ciprofloxacin Ali'timicrobial spectnwi: gram-negative aerobes: E. J/ili, Citrobacte1. Enterobacte1. Klebsiella, Proteus, &a!monella, Shigella, Vibrio, Yersinia, Aeromonas, rPasteurella, Pseudomonas, Haemophilus, Neisseria, Acinetobacter, Campylobacter, Providencia, . Serratia, Morgane/la, Legionella. Gra·m-positive aerobes: Staphy/ococci; various/y susceptible are Slreptococci. Indications: infections oj the ttrina,y tract, respiratory /raci, ears, nose and throat, gastro-intestinal tract and abdomen, hepatobilia,y ¦ tract, infection.s oj the bones and Joints and skin; gynecological infections and septicemia; treatment and prophylaxis oj i11fectio11s in. immunocompromised Suitable tor the most patients.Side effects: gastrointestinal disturbances, severe hospital patients dizziness, headache, jaligue, sensoria/ disorders, agitation, cmxiety, rare/y visua/ disturbances and and also tor out-patients conv11-lsious; a/lergic reactions, decrease oj b/ood pressure, paroxysma! tachycardia, pain in thejoin.ts, rare/y photosensitivity, transient changes in some !aborato,y valu.es. Risk oj c,ysta//uria with ins1.!Jicient intake oj liqu.id. lnteractions: antacids with AI auc/Mg hydroxides, theophylline, barbiturate narcotics. Note: caution in elderly palients and CNS disorders, reduced reaction capacity (synergy with alcohol). Co1ltrai1ldicatio1ls: hypersensitivity to qu.inolone chemotherapeutics, children in the age oj growth, pregnancy and lactation. Daily dosage: injectio11s ojthe !ower respirato,y tract (n.osocomial) 2 x 500 to 750 mg orally, 2 x 200 to 400 mg iv; infections ojthe lower u.rinmy tract 2 x 250 to 500 mg orally; uncomplicated infections ojthe upper urina,y tract 2 x 250 to 500 ·mg orai!y, 2 x 100 to 200 ·mg iv; complicated infections oj the upper urinary tract, bacteriemia, septicemla 2 x 500 to 750 mg ora/ly, 2 x 200 to 400 mg iv; osteomyelitis 2 x 750 mg orally, 2 x 200 to 400 mg iv; other injeclions 2 x 500 to 750 mg orally, 2 x 200 to 400 mg iv; chronic salnr:mella carriers 4 x 250 mg orally; acute gonorrhea a single dose oj 500 mg orally; in severe infections the oral dose can be increased to3 x 750 mg, and intraven.ous dose to 3 x 400 ·mg daily; dose is reduced in elderly ­patients and in severe renal d_ysfunction. Duration gg M of therapy: pyefonephritis at least JO days, peritonitis (in combination with metronidazole) at Jeast 14 days, osteomyelitis at least 6 weeks, other Reaches high concentrations i11fectio11s at feast 3 days after disappearance oj in body fluids, tissues and clinical signs. Supply: tablets: 250 mg JO tabs; 500 mg 10 tabs; injection: 100 mg/JO ml 5 ampoules. intracellular space. Ali additional information can be obtainedfrom the man1tfact1trer. ... KRK. SLOVENIA Systemic antimicrobial agent to.t..t:.:. ::: RADIOLOGY AND ONCOLOGY Established in 1964 as Radiologia Iugoslavica in Ljubljana, Slovenia. Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiophysics and radiation protection. Editor in chief Tomaž Benulic Ljubljana, Slovenia Associate editors Gregor Serša Ljubljana, Slovenia Viljem Kovac Ljubljana, Slovenia Editorial board Tullio Giraldi Udine, Italy Marija Auersperg Andrija Hebrang Ljubljana, Slovenia Zagreb, Croatia Matija Bistrovic Durila Horvat Zagreb, Croatia Zagreb, Croatia Haris Boko L 2 cm) or if they are in an unfavorable location ( e. g., in an intrahepatic duet or beyond a stricture). The endoscopic approach may be impossible when the normal anatomic relationship between the bile duet Corespondence to: Alojz Pleskovic MD, Medica! Fa­culty, Korytkova 4, 61105 Ljubljana, Slovenia. UDC: 616.366-003.217.7-089.879 and the duodenum is altered ( e. g., periampul­lary diverticulum) or when the sphincter can not be reached because of previous gastrointe­stinal surgery. Material and methods Between October 1988 and March 1992 we used ESWL to treat 16 patients who had resi­dual or primary bile duet stones after cholecy­stectomy. The patients were divided into two groups, 11 patients with residual bile duet sto­nes and 5 patients with primary bile duet stones after cholecystectomy. In both groups, the indi­cation for treatment was the failure of or anti­cipated difficulty with basket extraction of the stone. In five of these 16 patients, basket ex­traction via endoscopic sphincterotomy either had failed or had not been attempted because of the large size of stones (> 20 mm in three Extracorporeal shock -wave lithotripsy in the management oj' bile duet stones patients) or the presenee of an anato111ie ano­111aly (periampulary divertieulum in two pa­tients). Eleven patients had a T -tube in the bile duet, but basket extraetion via an endoseo­pie sphineterotomy was i111possible beeause the stones were in an unfavorable loeation (e. g., in an intrahepatie duet in six patients) or be­eause of the large size of the stones ( > 20 111111 in three patients) or beeause of a previous gastrointestial surgery (partial gastreetomy with Roux -en y anastomosis in two patients). Baseline blood studies, including laetie dehy­drogenase (LDH), aspartate transferase (AST), serum a111ylase, prothrombin tirne and partial tromboplastin tirne, and urinalysis were done less than 48 hr before ESWL and were repeated within 24 hr after the treatment. Abnormal tests were repeated until they returned to nor­mal. Bile drainage was tested for blood. Ali patients had a eoagulogram the day after the treatment and at least one more eholangiogram before diseharged or treated further. The study group included thirteen wo111en and three men (age range, 27-84 years). Most of the patients were more than 65 years old. The treatments were peiionned by using Sie­mens-Lythrotripter equipment. Results All stones were frag111ented suceessfully in 14 of the 16 patients. Fragmentation required one session in 12 patients, two sessions in one patient, four sessions in one patient. After ESWL, the stone fragments passed spontaneo­usly in nine patients. In five patients the frag­mented stones were removed by basket extrae­tion through the endoseopie sphineteroto111y. In two patients ESWL frag111entation failed and i111pacted stones in the pappila Vateri had to Pleskovic A and Jeleni! F be removed surgicaly. The patients remained in the hospital from 2 to 14 days after the procedure, depending mainly on whether addi­tional intervention was required. No clinically significant adverse reactions could be observed; in particular no evidence of pancreatitis was present. In two patients, transitory hemobilia developed. One patient had transient hematu­ria. Short -term e!evations of LDS and AST were observed in most of the patients. Bruising of the skin was seen in four patients, but none had significant pain (Figure 1--4). Figure 4. ERC after ESWL and extraction of frag­ments with Dorrnia basket. Figure 3. ERC showing a huge gallstone in the com­mon bile duet. shocks is therefore within the range of present Discussion practice. Pancreatitis, which has been described With the introduction of ESWL, another techni­in the treatment of gallbladder stones, has not que has become available for the nonsurgical been reported in patients in whom the treat­management of bile duet stones. 1 A prerequisite ment was pedormed for retained common bile for using ESWL in the treatment of bile duet duet stones, possibly because of the presence stones is the presence of a biliary drainage indwelling drainage tube. tube. This may be a T -tube or a nasobiliary The lack of clinically significant adverse re­tube. Such a tube is indispensable because actions to ESWL in our patients is in accor­unless the stones are calcified, they must be dance with the data reported in the literatu­ JO,ll visualized by injection of contrast material. re. However, the transient elevations of Dueta! stones rarely can be localized sufficiently LDH and AST -indicating !iver -celi damage by sonography. -may be related to the higher -tirno average The optimal or maximal number of shock number of shock waves used. Our rate of waves has not yet been definitely established. successful fragmentation of stones (88 % ) is Sauerbuch et. al. found that 500 -1500 shocks · about the same as that reported in the literatu­were sufficient to fragment the stones. Other re, the rate of spontaneous passage of fragments autors have reported the use of up to 3300 (56 % ) is also about the same as that found in 15 shocks.8• 9 Our use of between 1500 and 3000 other centres. 12· Exlraco,poreal shock -wave li1hotripsy in the management of bile duet stones Conclusion ESWL a is successful method for the manage­ment of patients with bile duet stones when used in conjunction with other nonsurgical teh­niques. References l. Sauerbrueh T, Delins M, Paumgartner G, et. al. Fragmentation of gallstones by extraeorporeal shoek waves. N Engl .I Med 1986; 314: 818-22. 2. Mulley AG. Shoek -wave lithotripsy: assessing a slam -hang teehnology. N Engl .I Med 1986; 314: 845-7. 3. Ferrueei JT. Biliary lithotripsy: what will the issues be? A .1 R 1987; 149: 227-31. 4. Burthenne HJ. The promise of extraeorporeal shoek -wave lithotripsy for the treatment of gallstones. A J R 1987; 149: 233-5. 5. Raskin JB. The eontinuing direet assault on the gallstone: enlightening, eleetrifying, and shoeking. Gastrointest Endosc 1987; 33: 262-3. 6. Nahrwold DL. Fragmentation of biliary traet sto­nes by lithotripsy using local anesthesia. Arch Surg 1988; 123: 91-3. 7. Van Sonnenberg E. Hofmann AF. Horizons in gallstone therapy -1988. A .I R 1988; 150: 43-6. 8. Sauerbrueh T, Stern M and the Study Group for Shoek -wave Lithotripsy of Bile Duet Stones. Fragmentation of bile duet stones by extraeorpo- real shoek waves. A new approaeh to biliary ealeuli after failure of routine endoseopie measu­res. Gastroenterology 1989; 96: 146-52. 9. Brown BP, Loening SA, Johlin FC. Dayton MT, Maher JW. Fragmentation of biliary traet stones by lithotripsy using loeal anesthesia. Arch Surg 1988; 123: 91-3. 10. Nieholson DA, Martin DF, Tweedle DEF, and Rao PN. Management of eommon bile duet stones using a seeond -generation extraeorporeal shoek­wave lithotriptor. B .! Surg 1992; 79: 811-4. 11. Weber J, Adamek HE, Riemann JF. Extraeorpo­ real piezoeleetrie lithotripsy for retained bile duet stones. Endoscopy 1992; 24: 239-43. 12. Staritz M, Grosse A, Alkier R, Krzaska B und Meyer zum Busehenfelde KH. Terapie der Chole­doehlithiasis dureh extrakorporale Stoswellenlitho­tripsie und adjuvante operative. Endoskopie. Z Gastroenterol 1992; 30: 156-61. 13. Binmoeller KF, Bruekner M, Thonke F, Soehen­dra N. Treatment of diffieult bile duet stones using meehanieal, eleetohyraulie and extraeorporeal shoek wave lithotripsy. Endoscopy 1993; 25: 201-6. 14. Lindstrom E, Boreh K, Kullman EP, Tiselius HG, Ihse l. Extraeorporeal shoek wave lithotripsy of bile duet stones: a single institution experienee. Gut 1992; 33: 1416-20. 15. Adamek HE, Buttmann A, Hartmann CM, Ja­kobs R und Riemann F. Extraeorporeal piezoelek­trisehe lithotripsie von intra-und extahepatisehen Gallengangssteinen. Dtsch Med Wschr 1993; 118: 1053-9. Radio/ Oncol 1994; 28: 178-82. Comparative assessment of three radiotherapy treatment protocols for inoperable cere bral metastases of non -small celi lung carcinoma Liliane Demange, 1 Alison Franks, 2 Xavier Panis1 1 Department of Radiotherapy and Oncology, Institut Jean-Godinot, 1, rue du General Koenig. 51056 Reims Cedex France 2 Yorkshire Regional Centre Far Cancer Treatment, Cookridge Hospital, Hospital Lane, Leeds LS16 62B Radiotherapy is often suggested in the treatment of inoperable brain metastases of non small cel! lung carcinoma. This retrospective study of 83 cases has enabled us to assess the survival of irradiated and not irradiated patients as well as the predictive factors of better outcome from treatment. Protocols delivering 30 Gy/10f/15d and 36 Gy/6f/25d lead to a significantly longer survival than the one delivering 20 Gy/5f/5d (p < 0,0005). A Good initial neurological status and the improvement of neurological signs after radiotherapy are two factors of favourable prognosis. However, tirne of onset of metastasis, histology, existence and number of extracerebral metastases have no influence on survival. We conclude that metastases must be irradiated early, as soon as the first neurological disorders appear. Treatment by irradiation of advanced metastases inducing major neurological disorders must be compared with the use of corticosteroids alone. Finally, we recommend the use of a dose greater than 20 Gy/5f/5d, with a fractionation adapted to the patient's neurological status. Key words: brain neopJasms-radiotherapy; neoplasm metastasis; carcinoma, non small celi Jung lntroduction Prognosis of patients with brain metastases of non-small celi Jung carcinoma (NSCLC) is poor and a majority of authors report a median 2 survival of 3 to 6 months. 1 · In case of a single operable metastasis, a combined surgery and radiotherapy allows for a significant increase in survivaJ; cases with a survivaJ of more than 10 Correspondence to: Xavier Panis M. D., Institut Jean­Godinot, 1, rue du General Koenig. 51056 Reims Cedex, France. 4 years have been reported.3· UnfortunateJy, routine practice shows that more than 75 % of cerebraJ metastases of non-small celi Jung carci­noma cannot be removed by surgery. These patients are refered for consideration of radio­therapy. In this study, we assess the survivaJ resuJts obtained by 3 different radiotherapy protocols among 83 patients with non-small celi lung carcinoma who were not suitable for surgery, in order to determine which patients will gain most from radiotherapy. The other aim of the study is to highlight the predictive factors of a UDC: 616.831-006.6-033.2:615.849:614.24-006.6 better survival. Radiotherapy 1rea1menl pro/oco/s for inoperable cerebral metastases Materials and methods Patients Eighty-three patients with brain metastases of 11011-small celi lung carcinoma were treated bet­ween January 1980 and December 1985. Me­dian age of the 79 male and 4 female patients was 61 years (range 37-83 years). Performance status according to Order's clas­sification5 (Table 1) showed 53 patients with Table l. Orclcr classification. Neurological grade Clinical conclition Normal physical and intellcctual activity. Normal ncurological condition. 2 Normal intellectual activity. Self-sufficient. Slight abnormalities at neurological examination. 3 Major neurological abnormalitics neccssitating hospital treatmcnt and medica! supervision. 4 Permanent hospitalisation. Serious physical ancl neurological condition minor neurological disorders (Order 1 and 2) and 30 patients with major neurological disor­ders (Order 3 and 4). In 5 patients, the brain metastasis was discovered before the lung carci­noma (revealing metastasis), in 37 simultaneo­usly (synchronous metastasis) and in 41, severa! months after the end of the bronchogenic car­cinoma treatment (secondary metastasis). Forty-four patients had an epidermoid carcino­ma, 20 an adenocarcinoma, 13 an undifferentia­ted carcinoma. Forty patients had a single me­tastasis, 43 multiple metastases. Brain metasta­ses were the only secondary location in 47 patients, while associated visceral metastases were present in 36 others. Treatment No surgery was possible for the metastases, either because of their multiple locations, or because of the poor performance status of the patients. Ali patients received corticosteroids for at least one month. Fifty-nine patients also had cranial irradia­tions. In ali patients, radiotherapy was given to the whole brain using two lateral opposing fields of l.25 MeY photons (Cobalt 60). Three protocols were used, according to the individual choice of the radiotherapists: -Protocol A: 20 Gy/5f/5d (5 fractions of 4 Gy in 5 days) -Protocol B: 30 Gy/10f/15d (10 fractions of 3 Gy in 15 days) -Protocol C: 36 Gy/6f/25d (2 courses of 3 fractions of 6 Gy in 3 days with an interval of 3 weeks). Seventeen patients were treated with protocol A, 18 with protocol B, 24 with protocol C and 24 with corticosteroids only. Evaluation Response to the treatment has been evaluated in terms of neurological perfonnance status and survival time. Performance status according to Order's clas­sification was assessed just before and three weeks after radiotherapy. Performance status was considered to have improved when it de­creased at least one class, to have worsened when it increased at least one class, and to have been stable when its class did not change. Survival time was assessed from the diagnosis of brain metastasis, and survival curves were drawn up using the Kaplan-Meier method. Pre­dictive factors were studied and distributional comparisons were made by the use of the log-rank and chi-square tests.6 Results Ali patients died, the majority from their brain metastasis. Overall median survival was 95 days, 25 days for those treated with corticoste­roids alone and 105 days for those treated by radiotherapy. Demange L et al. Quality of response to radiotherapy After radiotherapy, neurological status impro­ved in 32 patients (54 % ), was stable in 22 patients (38 % ) and worsened in 5 patients (8%). Median survival was 150 days for patients whose condition improved, 60 days for patients whose condition was stable and 30 days for patients whose condition worsened. The difference in survival between patients whose condition improved and the others (those whose condition was stable or worsened) was statistically significant (p < 0,025). Radiotherapy protocols Median survival was 60 days for patients treated with protocol A (20 Gy/5f/5d), 99 days for those treated with protocol B (30 Gy/10f/15d) and 125 days for those trated with protocol C (36 Gy/6f/ 25d) (Table 2). Whilst difference in survival is not statistically significant between the two pro­tocols that resulted in the longer survivals (B and C), it is statistically significant between protocol A and the other two (B and C) (p < 0,0005). We did not find any statistically significant survival difference between patients treated with corticosteroids alone (25 days) and those treated with protocol A (60 days). Moreover, radiotherapy is most efficient in patients with a good neurological condition. Thus, median survival for Order 1 and 2 pa­tients was 25 days when untreated and 125 and 150 days respectively when treated with 30 Gy/ 10f/15d and 36 Gy/6f/25d. While median survi­val with, or without, radiotherapy was 25 days for Order 3 and 4 patients. Other factors that influence the quality of response to treatment Factors such as tirne between discovery of me­tastasis and that of Jung cancer (tirne of onset of metastasis), histological status, number of metastases, presence or absence of extracere­bral metastases did not result in any statistically significant difference. However, difference in survival was significantly greater in patients with a good neurological condition (Order 1 and 2) compared to others (Order 3 and 4) (Table 2). Table 2. Study of predictive factors of the quality of response to radiotherapy according to median survival. Median Factors studied survival Protocol of radiotherapy -20 Gy/5f/15d 60 days -30 Gy/10f/15d 99 days p<0,0005 -36 Gy/6f/25d 125 days Time of onset of metastasis -revelatory 150 days -synchronous 90 days NS -secondary 25 days Histology -epidermoid carcinoma 90 days -adenocarcinoma 70 days NS -undiffentiated carcinoma 70 days Number of metastases -one 99 days NS -severa! 70 days Extracerebral metastases (EM) -withoutEM 30 days NS -with EM 98 days Neurological status at diagnosis -Order 1 and 2 95 days P < 0,025 -Order 3 and 4 25 days NS = non significant Discussion Use of radiotherapy for the treatment of non operable cerebral metastases of NSCLC allows for better survival than use of corticosteroids alone. In our study, the conditions required for obtaining a better result were the use of a dose greater than 20 Gy/5f/5d and a neurological status which was not seriously impaired. In the literature, most of the series published analyze the results of a radiotherapy treatment on cerebral metastases whatever their origin. One of the characteristics of our study is that we examined a group of patients with cerebral metastases of an homogeneous origin (NSCLC) Radiotherapy treatment protocols for inoperable .cerebral metastases to determine the predictive factors of a better response to treatment. Moreover, each of the radiotherapists in our team fallowed invariably his own protocol in the treatment of cerebral metastases, a habit which facilitated our compa­rison of the results of the three protocols. Improvement of survival by radiotherapy treatment of non operable metastases of NSCLC has been reported by severa! authors with median survivals of 3 to 4 months from 7 10 discovery of cerebral metastasis,5• -close to the figures detennined by our study. It is also faund in the literature that radiotherapy induces longer survivals in patients with a good neuro­logical status (Order 1 and 2).5• 7-10 Our study, and those of Newman7 and Franchin,9 conclude that best results occur when radiotherapy allows the patients to maintain or to recover a good neurologic status (Order 1 and 2). Median survival is, in our study, influenced by the radiotherapy dose. An analysis of the results of the three protocols we used (20 Gy/5f/ 5d, 30 Gy/10f/15d, 36 Gy/6f/25d) confirms a sig­nificantly longer median survival far the proto­cols using 30 Gy/10f/15d and 36 Gy/6f/25d. Im­provement of survival when using higher doses far cerebral metastases of NSCLC has been 10 analyzed by other authors.7• 8• Newman 7 re­ports a better survival when the dose used is greater than 40 Gy/20f/28d. Chatani,8 in a ran­domized study, faund a significantly improved survival (p < 0,05) when applying 50 Gy/20f/28d than when applying 30 Gy/10f/15d. Egawa10 ob­serves a correlation between the dose applied and the median survival: 0.6 month with doses lower than 30Gy, 1.7 months far doses in the 30-50 Gy range and 4 months far doses of more than 50 Gy. Improvement of survival far higher doses has led to the accrual of a series of 44 patients requiring re-irradiation (among whom 15 had metastases from NSCLC) .11 After a first treatment with 30 Gy, the patients received a second course of irradiation resulting in a total dose of 60 Gy. Unfartunately, the additional treatment was seldom advantageous; survival after irradiation being generally short, and ra­rely improved in quality. Finally, a significant number of survivors after reirradiation died from cerebral necrosis. Therefare, the authors conclude in suggesting that a higher total dose with a conventional fractionation be used far the initial treatment of cerebral metastases. Similarly, it should be noted that the addition of a chemotherapy to radiotherapy12 in the treatment of cerebral metastases of bronchoge­nic carcinoma results in a higher tumour regres­sion rate than that obtained with radiotherapy alone, although survival is not improved. The analysis of other parameters that could have an influence on survival of inoperable metastases of NSCLC shows no difference ac­cording to relative times of onset of metastasis and bronchogenic tumour, histology and num­ber of metastases. These results are faund as a 3• 5, 7-lO, 13, 14 recurring feature in the literature.It must be emphasised that the longest survivals of patients with a single metastasis, faund by De viri, 15 benefit from the fact that those single metastases could be treated by surgery. The lack of influence on survival of the presence of extracerebral metastases associated with cere­bral metastases is consistent with the results of other studies;5 however, it must be said that in his conclusions, Robin14 faund a better survival far cerebral only metastases. Finally, it appears that the radiotherapy treat­ment of inoperable metastases of NSCLC must not be fixed and must firstly take into account the patient's neurological status. The dose deli­vered must be high enough to be effective. One could recommend a high and concentrated dose ( e. g. 36 Gy/gf/25d) far patients with a bad neurological status, and a high but fractionated dose ( e. g. 30 Gy/6f/15d) far those with a better neurological status. In patients with a very poor perfarmance status, radiotherapy must be con­sidered versus steroids alone. However, when radiotherapy is used, metastases should be irra­diated as soon as possible when neurological symptoms develop. References l. Ballantine HT, Byron FR. Carcinoma of the lung with intracranial metastasis. Arch Surg 1942; 57: 849-54. Demange L et al. 2. Perese DM. Prognosis in metastatic tumors of the brain and the skuti. An analysis of 16 operative and 162 autopsied cases. Cancer 1959; 1.2: 609-13. 3. Galichich JH, Sundaresan N, Arbit E and al. Surgical treatment of single brain metastasis: fac­tors associated with survival. Cancer 1980; 45: 381-86. 4. Mussi A, Janni A, Pistolesi M, Ravelli V, Buona­guidi R, Angeletti CA. Surgical treatment of primary lung cancer and solitary brain metastasis. Thorax 1985; 40: 191-93. 5. Posner JB. Management of central nervous system metastases. Semin Oncol 1977; 4: 81-91. 6. Kaplan EL, Meier P. Non parametric estimation from incomplete observation. / Amer Stat Assoc 1958; 53: 457. 7. Newman SJ, Hansen HH. Frequency, diagnosis and treatment of brain metastases in 247 consecu­tive patients with bronchogenic carcinoma. Cancer 1974, 33: 492-96. 8. Chatani M, Teshima T; Hata K, Inouet T, Suzuki fr lung carcinoma. Acta Radiologica Oncology 1985, 24: 311-14. T. Whole brain irradiation for metastases om 9. Franchin G, Minatel E, Roncadin M, Trovo M, et al. Accelerated split course regimen in the treatment of brain metastases. Radiother Oncol 1988, 1.2: 39-44. 10. Egawa S, Tukiyama I, Akine Y, Kajivra Y, et al. Radiotherapy of brain metastases. lnt J Radiat Oncol Biol Phys 1986, 1.2: 1621-25. 11. Hazuka MH, Kinzic JJ. Brain metastases: results and effects of re-irradiation. lnt 1 Radia/ Oncol Biol Phys 1988; 1.5: 433-37. 12. Ushioy, Aritan, Hayakawa T. Chemotherapy of brain metastasis from lung carcinoma: a controlled randomized study. Neurosurgery 1991, 28: 201-10. 13. Sundaresan H, Galichich JH, Beattie EJ. Surgical treatment of brain metastasis from lung cancer. J Neurosurg 1983, 58: 66-71. 14. Robin E, Bitran JD, Golombs HM, et al. Progno­stic factors in patients with non small celi broncho­genic carcinoma and brain metastasis. Cancer 1982, 49. 1916-19. 15. Deviri E, Schachner A, Havely Y, Shalit M, Levy MJ. Carcinoma of lung with a solitary cerebral metastasis. Surgical management and review of the literature. Cancer 1983, 52: 1507-09. Radio! Oncol 1994; 28: 18 3-7. Adjuvant treatment of malignant melanoma with interferon after radical surgery -part II. Effect of recombinant alpha interferon Zvonimir Rudolf Institute of Oncology, Ljubljana, Slovenia In our randomized prospective study, patients with malignant melanoma were treated with both human leukocyte interferon alpha (HulFN) and recombinant interferon alpha 2b (lntron) after surgical removal of primary tumor ( Clark leve! of in vas ion IV, V and/or thickness exceeding 1.5 mm). They were randomized into two arms: (1) those treated with HulFN•or with lntron; and (2) a control group with no immediate treatment. Interferon was applied through 30 weeks. Cumulative dose for HulFN was 6 X 107 U (2 x 1a6 U weekly), and for lntron 9 x 107 U (3 x 1a6 U weekly). Both arms of the study included altogether 421 patients: 161 in the control group, 160 in the HulFN group, and 100 patients in lntron group. The results of 5-year analysis showed significant differences in the disease-free interval as well as in survival between both arms in favour of interferon (both HulFN and lntron) treated patients (p < 0.005). According to stratification by sex, the difference was significant also between Jemale as well as male patients, of both groups (p < 0.005). In a majority of patients interferon application caused a flu-like syndrome, whereas adverse effects on blood count and chemistry could not be established. The treatment (given in the reported dose) was not toxic and was applied on an out-patients basis. Key words: melanoma-drug therapy; interferon-alpha; interferon alfa, recombinant lntroduction In the world, patients with malignant melanoma of the skin represent approximately 1 % of ali cancer patients. The incidence of melanoma has been rapidly increasing, doubling its value every 6-10 years, and likewise, also melanoma­related mortality has been exhibiting a trend of 2 constant increase. 1• Correspondence to: Prof. Zvonimir Rudolf, MD, PhD, Institute of Oncology, Zaloška 2, 61105 Ljublja­na, Slovenija, Tel. + 386611314 225, Fax + 386611314180 . Considering the high mortality rates observed in patients with malignant melanoma (with deep level of invasion) as well as ineffective treat­ment of advanced disease, many studies have been investigating the potential of various treat­ment modalities. Since the results of malignant melanoma treatment are stili unsatisfactory, especially in advanced stages of disease, an effort should be directed to earlier treatment. Unfortunately, the results of adjuvant treatment in the early stage of the disease with chemotherapy3 have also not confirmed the effectiveness of treat­ UDC: 616.5-006.81-0 85 ment so far. 184 Rudolf Z During the last decade a number of clinical studies have been performed to investigate the therapeutic potential of interferons in the treat­ment of various malignant diseases.4 Although partial and occasional complete regressions have been observed in some cancer patients,5 the overall results of single-agent interferon treatment point out the need for further clinical and laboratory research in order to establish the role of interferon in cancer treatment, par­ticularly in solid tumors. In view of the previously mentioned facts, we decided to established the role of interferon as an adjunct to surgical treatment of primary malignant melanoma. A prospective randomi­zed trial6 was commenced in 1988 in patients with malignant melanoma stage IIA and B according to the AJCC classification.7 In our randomized prospective study, patients with malignant melanoma were treated with human leukocyte interferon alpha (HuIFN) af­ter surgical removal of primary tumor (Clark level of invasion IV, V and/or thickness excee­ding 1.5 mm). They were randomized into two groups: (1) those treated with HuIFN and (2) a control group with no immediate treatment. HulFN was applied through 30 weeks in cum­mulative dose 6 x 107 U, and 2 x 106 U weekly. Both arms of the study included altogether 321 patients.8 The results of general analysis showed signi­ficant differences in the disease-free interval as well as in survival between both groups in favour of HuIFN treated patients (p < 0.005). La ter in the study, a group of patients treated with recombinant alpha interferon was added. In this report the analysis and comparison of various treatment modalities is presented. Patients and methods In the protocol only patients with histologically proven primary tumor after radical surgery were included. As mentioned previously, ali the pa­tients were in Stage IIA and IIB of the disease which means that the primary tumors were classified as Clark IV, V level of invasion and/or tumor thickness exceeding 1.5 mm. The patients were randomized into two protocol arms -those treated with HuIFN or Intron and control group with no immediate treatment after radical surgery (Controls). Ali patients in both arms were on regular­clinical follow-up. Complete bloods counts, b\ood chemistry, renal and !iver functin tests were taken each check; these were performed monthly in the first 2 years, and later on in 2 month intervals. Complete evaluation of pa­tients was done before and after therapy. Pa­tients with relapse (in both groups) were further treated as necessary (with surgery, radiothera­py, chemotherapy) and were afterward also on regular follow-up. Treatment -Treatment in the first group of patients consisted of i/m paplication of crude human leukocyte interferon (Imunološki zavod, Zagreb, Croatia) and started within the first month after surgical excision. Interferon was applied for 30 weeks in cumulative dose of 6 x 107 units. Each patient received 2 X 106 units of interferon weekly. Similar regimen was applied in the second group of the treatment arm. In this group the treatment consisted of i/m application of Intron; the drug was applied for 30 weeks in cumulative dose of 9 x 107 units and each patient received 3 X 106 units of intron weekly. HulFN group -A total of 160 patients, 70 males and 90 females, have been entered into the HuIFN group. The mean age of patients was 48 years (48 ± 14 years, range 20-78 years). The patients were distributed according to the primary tumor site as follows: head and neck region (HN) -15; trunk (T) -79; limbs (L) ­ 66. Primary tumors were determined as super­ficialy spreading type (SSM) in 31 cases, nodu­lar type (NM) in 127 cases and lentigo maligna type (LMM) in two cases. The leve! of invasion was Clark IV in 109 cases, and Clark V in 12 cases. In 39 cases the level of invasion was Clark III, but tumor thickness exceeded 1.5 mm, which was in accordance with the pro­tocol criteria. Adjuvant treatment of malignant melanoma with inte1feron after radical surgery lntron group -A total of 100 patients were included in this group, 45 males and 55 fernales. Mean age of patients was 48 years (48 ± 14 years, range 20-73 years). The patients were distributed according to the primary site as follows: HN -6; T -54; L -40. Primary tumors were determined as SSM type in 19 cases, NM in 79 cases and LMM in two cases. The leve! of invasion was Clark IV in 66 cases and Clark V in 5 cases. In 29 cases the leve) of invasion was Clark III, but tumor thickness exceeded 1.5 mm. Control arm -The control arm comprised 161 randornly selected patients (71 males and 90 fernales) in the mean age of 52 years (52 ± 13 years, range 21-84 years). As to the prirnary tumor site, lesions were located in head and neck region in 16 cases, on the limbs in 70 and on the trunk in 75 cases. In 92 patients tumors were assessed as SSM type, in 3 patients as LMM and in 66 patients as NM type. The leve! of invasion was Clark III in 23 cases (but thickness more tlian 1.5 mm), Clark IV in 101 cases, and Clark V in 12 cases. Patient distribution by various potential prog­nostic factors is presented in Table l. Our analysis showed that ali protocol groups, i. e. HuIFN, lntron and Controls, were similar as to their sex and age distribution. Also, there Table l. Comparison of HuIFN, Intron and Control groups according to the sex and age distribution, type ancl site of primary tumor and the leve! of invasion. HulFN lntron Controls No. % No. % No. % RADICAL EXCISION Clark IV.V and/or thlckness > 1.5 mm randomlzation TREATMENT ARM CONTROL ARM INTRON 6 3 X 10 U!Week 30 weoo FOLLOW-UP treatrnent as necessary D F 1 SURVIVAL Figure l. Protocol summary. was no major difference in the site and type of primary tumor, and neither in its leve! of inva­sion. Statistical analysis -The statistical analysis was done using the Kaplan-Meier product-limit method9 • 10 which is a non-parametrical method to estimate the probability of an event occuring during a given tirne-interval. Statistical signifi­cance of graphed survival curves was tested using logrank program which perforrns a chi­square-like analysis.11• 12• t3 Results 71 44 Sex M 70 44 Survival analysis 56 55 55 90 F The analysis of survival in both protocol arms Age 100 63 64 64 81 50 >53 60 37 36 36 80 50 is presented in Fig. 2. The difference between Type NM 127 79 66 41 both treated groups and the controls is signifi- SSM 31 20 19 19 92 57 cant (Intron curve vs. Controls curve and LM 2 1 2 2 3 2 HuIFN curve vs. Controls curve, p < 0.01). Local. Trunk 47 HNeck 15 9 6 6 16 10 There was no difference between both treat- Limbs 68 40 40 70 43 ment groups, i. e. Intron and HulFN. Clark III 39 29 29 38 23 IV 109 68 66 66 101 62 Since the localization of primary tumor could v 12 8 5 5 12 7 influence the survival, the patients were analy- Tota! 160 100 100 100 161 100 zed by grouping according to the primary site. 186 Rudolf Z 1.0 -.....---- -- ------------7 0.5 * -CONTllOLS o · HulFN x -lnf(()O % SURVIVAL months 50 100 150 Figure 2. The comparison of survival between patients in control group, patients treated with human leuko­cyte interferon alpha and patients treated with recom­binant interferon alpha 2b. (Controls -control group, HuIFN -patients treated with human leukocyte interferon alpha, Intron -pa­tients treated with recombinant interferon alpha 2b; the difference between HuIFN and controls as well as between Intron group and controls is significant, p<0.05). No difference could be established between patients with primary tumor in head and neck region, limbs, or trunk. The possible influence of age on survival was analyzed. Between the groups of patients trea­ted with Intron age more and less then 53 years no diference could be noted. Analysis of survival according to stratification by tumor type was performed, and there was no difference in survival between patients with nodular, lentiginous or superficial spreading type. The difference between patients treated with intron and control patients was significant also by sex stratification (Fig. 3). Fernales in the treated group had better survival than fernale controls; likewise, male patients treated with intron survived longer than male patients in the control group (Intron females curve vs. Control females curve, and Intron rnales curve vs. Con­trol rnales curve; p . 0.05). * -CONTllOL females o -CONTllOL males x -INTllON males -INTllON females Figure 3. The comparison of survivals between Intron group and controls by sex stratification. (Control females -temale controls, CONTROL males -male controls, Tntron females -female patients treated with recombinant interferon alpha 2b, Intron males -male patients treated with recombinant inter­feron alpha 2b). Interferon treatment was well tolerated by the majority of patients and no patient refused it because of toxic side effects. In ali patients the application of interferon was followed by mild up to moderate fever (less than C) 39° which was transient. The patients also experien­ced flulike syndrom, which was anticipated. The application of interferon in the stated do­sage exerted no effect on blood count and chemistry. In one case, as reported previously, 14 a moderate allergic reaction manifested with urticaria followed the second course of treat­ment in the HuIFN group. Since the fever and flu-like syndroma were transient, after pilot study it was decided that the regimen should be applied on an out-patients basis. Discussion The increasing incidence of melanoma and its tendency to affect younger adults, as well as relative ineffectiveness of treatment in advan­ced stages, point out the need for an effective adjuvant therapy. Adjuvant treatment of malignc1111 melanoma with inte1feron after radirnl surgery In our study, both treatment regimens (i. e. HuIFN and Intron) resulted in prolongation of the survival of patients, since the difference between both protocol groups when compared with the controls (HulFN vs. Controls as well as Intron vs. Controls) was significant. In addi­tion, the difference between male as well as female patients of both groups was also signifi­cant. According to these results, it can be postulated that the interferon (both HuIFN and recombinant alpha interferon) treatment pro­longed the survival of patients in treated groups. Also, the treatment was not associated with significant toxic side effects. Possible mechanisms of interferon action have not been fully explained yet. Theoretical­ly, interferons could exert their antitumor ef­fects in three ways: (1) via the host immune system; (2) by altering some non-immune host/ tumor celi interactions; or (3) by direct effects on the tumor cells. Data from laboratory animal experiments suggest that interferon act best when tumor load is low, such as was the situa­ 8 tion in our study.6• Interferons are also an important part of lymphokine cascade. It is reasonable to conclude, that interferon could act as a biological response modifier through many yet uknown mechanisms including lym­phokine cascade. According to our results, the adjuvant inter­feron (both HuIFN and Intron) treatment can be advised in cases with prognostically unfavou­rable melanoma, i. e. primary melanoma tu­mors with Clark IV, V leve! of invasion and/or a thickness more than 1.5 mm. Acknowledgement The financial support by grant No. C3-0563-302/ 27-40/B of the Ministry of Science and Teclmo­logy of Slovenia is gratefully acknowledged. References l. Cancer incidence in Slovenia, 1980, 1981, 1982, 1983, 1984, 1985, 1986. Ljubljana: Institute of Oncology-Cancer Registry of Slovenia, 1984, 1985, 1986, 1987, 1988, 1989, 1990. 2. Rudolf Z, Roš-Opaškar T. Survival and disease­free interval of malignant melanoma patients in relation to the prognostic factors. Radio/ Oncol 1992; 26: 45-55. 3. Koh HK, Sober AJ, Harmon DC, Lew RA, Carey RW. Adjuvant therapy of cutaneous malig­nant melanoma -a critical review. Meclical and Pediatric Oncol 1989; 13: 244-60. 4. Baron S, Tyrring SK, Fleischmann R, Coppenha­ver DH, Niesel DW, Klimpel GR, Stanton JG, Hughest TK. The interferons -mechanisms of action and clinical applications. JAMA 1991; 266(10): 1375-83. 5. Kirchner H. Update on interferons. Progress in Oncology 1988; 7: 5-62. 6. Rudolf Z, Furlan L. Adjuvant treatment of malig­nant melanoma with human leukocyte interferon. Period Bial 1990; 92(1): 141-2. 7. American Joint Committee on Cancer: Manual far staging af cancer, 3rd ed. Philadelphia: JB Lippincott, 1987. 8. Rudolf Z. Adjuvant treatment of malignant mela­noma with human leukocyte interferon after radi­cal surgery: l. general analysis. Radio/ Oncal 1993; 27: 332-8. 9. Kaplan EL, Meier P. Nonparametrie estimation from incomplete observations. 1 American Statisti­cal Assaciatian 1958; 53: 457-81. 10. Matthews DE, Farewell VT. Using and u.nderstan­ding medica/ statistics. Karger, 1988, 67-78. 11. Peto R, Pike MC. Design and analysis of rando­mized clinical trials requiring prolonged observa­tion of each patient: T. lntroduction and design. Br 1 Cancer 1976; 34: 585-612. 12. Peto R, Pike MC. Design and analysis of rando­mized clinical trials requiring prolonged observa­tion of each patient: II. Analysis and examples. Br 1 Cancer 1977; 35: 1-39. 13. Anderson S, Auquier A, Hauck WW. Statistical methads far comparative studies. J Wiley, 1980, 199-234. 14. Rudolf Z. Treatment of malignant melanoma with htJman leukocyte interferon -preliminary results of randomized tria!. Filipic B(ed): Yugoslave col­loquium on interferon. Ljubljana, Slovenian Mi­crobiological Society 1986, 129-33. Radio/ Oncol 1994; 28: 188-93. Oromandibular reconstruction with microvascular osteocutaneous free flap (report of twenty cases) Marijan .ar,1 Mirna Juretic,1 Hrvoje Štalekar,2 Zoran Žfaljardic,1 Zarko Tomljanovic, 2 Ivo Rakulic, 2 Ivan Luštica Clinical Hospital Center Rijeka, 1 Department oj Maksillojacial Surgery, 2 Department oj 3 Traumatology, Department oj Otorhinolaryngology, Croatia Twenty patients with oral cancer who undervent Commando operation and postoperative reconstruc­tion of the oromandibular defect with microvascular osteocutaneous free flap have been reported. Eight metatarsal, seven radia! and five fibular microvascular osteocutaneous free flaps were used, being successfully performed in 18 (90 %) patients. Each of the tree flaps used, was characterized by some advantages and disadvantages. Fibular microvascular osteocutaneous free flap has been the best for the mandibular reconstruction at any rate, because of the posibility of taking a great part of the bone and reconstruction of the largest defects and even the whole mandible. Use of metatarsal microvascular osteocutaneous free flap has been limited to smaller mandibular defects only, while the radia! microvascular osteocutaneous free flap developed very severe and a long -term morbidity of the donor site. Key words: oral cancer; mandibular neoplasms-surgery; surgical flaps; microvascular osteocutaneous free flaps Introduction Primary reconstruction of partial mandibular defect has not been considered to be necessary for years. Later, the defects have been recons­tructed in different ways and with various suc­cess. Using various plates (A-0 system, Thorp and others), the reconstruction was successful in 73 % to 100 % , ranging from 40 % to 70 % Correspondence to: Doc dr. sci. Marijan Car, 5126 Crikvenica, Basaricekova 2, Croatia. Tel.: (051) 781 538. UDC: 616.716.4-006.6-089.843 with nonvascularized bones, bone grafts or pe­dicled osteomiocutaneous flap. 1 Urken L reports data showing 96 % of success at partial mandibular defect reconstruction with vascularized osseous composite free flaps in 322 published cases between 1986 and 1990. Primary oromandibular defect reconstruction following radical tumour excision leads to the most rapid healing and recovery of the patient to a normal life. The increased number of the surviving pa­tients after reconstructions in the oral cavity with the microvascular osteocutaneous free flaps has been accompanied by significant fun­ctional improvements and aesthetic results.1 Oromandibular reconstruction with microvascu/ar osteocutaneous free flap Good vascularization, sufficient three -di­mensional bone size, similarity to the mandibu­lar shape, facility of forming and transfering of . the flap without compromised vascularization, as well as minimal donor site morbidity and the possibility of two medical teams (maxillofacial and microsurgical) working at the same time to shorten the operation time, are the greatest advantages of vascularized osseous composite free flaps. The purpose of this paper is to present our experience with oromandibular defect recons­ tructions with microvascular osteocutaneous free flaps from foot, lower leg and foream, the osseous parts of which are the second metatar­ sal bone, the fibula and the radius. Materials and methods From January 1990 to December 1991, twenty previously untreated patients with oral cancer were operated at Department of Maxillofacial­ Surgery, Clinical Hospital Center in Rijeka. Ali treated patients were males, 40 to 70 year old. Fourteen of them were smokers consuming more then twenty cigarettes per day; five pa­ tients gave up smoking, while one of them was a 11011 smoker. Nine of them were alcoholics, nine patients consumed alcohol occasionaly, and two of them were abstinents. Half of them suffered from hypertension and various cardiac disturbances; two patients suf­ ferred from obstructive chronic respiratory dis­ turbances and one from mild form of diabetes. Ali tumors were histologically confirmed as planocellular carcinomas. Out of twenty operated patients, fifteen were classified as T4 Nl M0, four as T4 N2 M0 and one as T4 N3 M0. Tumors were localised on the floor of the mouth and the tongue in nine cases, the flooer of the mouth and the mandibular gingiva in six, retromolary in four, and on the buccal mucosa, floor of the mouth and the mandibular gingiva in one. Ali tumours involved the mandibular bone. Ablative part of operation was performed by maxillofacial surgeons, while the primary re­construction was carried out by teain of micro­vascular surgeons. All patients underwent Commando opera­tion, i.e., the radical tumor excision, partial resection of mandible and the radical neck dissection together with neck blood vessels (ar­teries and veins) preparation for microsurgical anastomosis. A part of mandibular corpus was resected in ali 20 patients; in two of them, resection was extended to the mandibular ramus and in one nearly whole was resected. Seven patients underwent tracheotomy. Microvascular osteocutaneous free flaps were taken from feet -second metatarsal bone (Fi­gure 2) in eight patients, from lower leg -fibula (Figure 3) in five and from the forearm -radius r Figure l. Bone angulation of the microvascular osteo­cutaneous free flap. Car Met. al. Figure 3. Fibular microvascular osteocutaneous free flap. (Figure 4) in seven patients. Selection of parti­cular flap depended on the extent of the oro­mandibular defect. Microvascular osteocutaneous free flap from the toot usually served tor the smallest mandi­bular defect reconstructions because of limited length of the second metatarsal bone and the corresponding skin. Larger mandibular defects were reconstruct­ed with radia! microvascular osteocutaneous free flaps usually taken from the left torearm, while fibular microvascular free flaps were used tor reconstruction of defects when almost whole mandible had to be replaced. Osteosynthesis was predominantly carried out by a wire or a plate with screws. Seventeen patients underwent bone angulation (Figure 1) in order to from the angle of mandibule and chin. It was done by a traiangular osteotomy, and the angulation achieved, was fixed by two wires. Intermaxillary fixation was set in these cases. Soft tissue defect in the oral cavity was cover­ed with the skin from the microvascular osteo­cutaneous free flap. Anastomoses were carried out to the superior thyroid and the facial arteries and the external jugular and the facial veins (Table 1). Two patients underwent double vein anasto­mosis. Anastomoses to arteries and facial veins were always pertormed at the opposite side of the neck from the postoperative defect. Donor site skin defects were covered with Thiersch grafts. Forearm defects were succes­sfully closed with local flaps. 2 lmmobilization was pertormed each titne using a plaster splint and the Kirschner wire splint on the toot. Ali the flaps were followed up regularly in the course of the first five consecutive days. Further controls were done by maxillofacial surgeons. Table l. Recipient blood vessels of the neck. B loocl vessels Number % Arteries thyreoidea superior 16 80 facialis 4 20 Tota! 20 100 -- Yeins jugularis externa 16 73 facialis 4 18 transversa colli 2 9 Tota! 22 100 Table 2. Eficiency of microvascular osteocutaneous free flap transfers. Flap Successful lneffectual reconstruction ­ reconstruction ­ accepted flap rejacted flap Number % Number % Metatarsal (n = 8) 8 100 o o Radia! (n = 7) 6 86 1 14 Fibular (n = 5) 4 80 1 20 Tota! (n = 20) 18 90 2 10 Oromandibular reconstruction with microvascular osteocutaneous free flap Results Out of 20 microvascular osteocutaneous free flap transfers, 18 (90 % ) were successfully done while two of them (10 % ) failed (Table 2). Microvascular osteocutaneous free flap tran­sfers were followed by various complications (Table 3). Except partial dehiscence at the flap border the most frequent complications during the postoperative course were neck infections and fistulae appearing in connection with them. Dehiscences at the flap border were refreshed and sutured. Infections were successfully treat­ed by high doses of antibiotics. Fistulae were closed with local flaps in five patients, while the pedicled flap (latissimus dorsi) was used once for the fistula closure. Intraorally exposed bone or osteosynthetic material was covered by local mucous mem­brane flap under local anestesia. Ali operated patients were monitored for blood circulation in the flap. Revision of micro­vascular anastomosis during the 24 hours was needed in four patients. Two flaps falied and were taken away while Table 3. Postoperative complications following micro­vascular osteocutaneous free flap transfers. Complications Number % derwent the transfer of the metatarsal microvas­ At the recipient site cular osteocutaneous free flap. These disturban­ Partial dehiscence at the flap border 9 45 ces appeared as the consequence of ischemia Neck infection 6 30 Fistula 6 30 in the foot after removal of peroneal and dorsal lntraoral bone exposure 2 10 metatarsal arteries. Intraoral plate exposure or the wire The opertion Jasted from 6 to 10 hours and of osteosynthesis 3 15 was followed by severa! microvascular revisions and postoperative complications. Two medica! Microvascular Revision of microvascular anastomoses 4 20 teams always worked together. Partially failed flap 3 15 The tirne of hospitalization depended on the Completely failed llap 2 10 operation efficiency and postoperative compli­ the defects were covered with pedicled flaps (pectoralis major -myocutaneous flap). Superficial marginal necrosis, which occured in three patients, healed secondarily without any consequences. We had more donor site complications, espe­cially on the forearm after the radia[ micro­vascular osteocutaneous free flap transfer, in­cluding three fractures of the radius. These fractures occurred as the consequence of the specific osteotomy, the ischemic changes in the remaining radius, the age of patients and poor postoperative immobilization. Decay of skin cover with Thiersch graf at the same donor site during the postoperative course led to denuda­tion of tendons in four patients. Shrivelling, weakened mobility and impaired finger grip occurred. Denuded tendons were covered with new Thiersch graf. We tried to slove the defect of soft tissues of the forearm with local flaps, after the flap had been taken. In this way better results were obtained.2 The aforementioned complications in our se­ries resulted in weakened mobility, grip and pressure of fingers up to 50 % in six patients after the radia! microvascular osteocutaneous free flap had been transferred. Eight patients developed gait disturbances; four of them after the fibular microvascular osteocutaneous free flap transfers and the remaining four who un­ At the donor site Haematoma Seroma Infection Gait disturbances Denuded arm tendons cations. Other factors influencing the duration of hospitalization were age, general condition 2 2 4 10 10 20 and other diseases of the operated. The shortest hospitalization tirne among the patients who 8 40 underwent Commando operation and the pri­ 4 20 mary reconstruction, was 10 days. Fracture of the radia! bone 3 All the presented patients have been regu­ 192 Car Met. larly controlled, being ali alive. In two of them with microvascular osteocutaneous free flaps (radia! and fibular), where the defect was sub­sequently reconstructed by pedicied flaps, fun­ctional and cosmetic results were poor. In the remaining 18 patients, the appearance, speech and swallowing were satisfying. Four of them have been wearing lower pro­theses accompanied by more or less disturban­ces. Metastases were faund on the opposite side of neck in three patients in the tirne interval from 6 to 12 months. Two of them underwent functional and one radical neck dissection. Discussion When malignant aggressive disease, such as the oral cancer, is in question, the progressive invasion and erosion of the face represent the worst problem. Radical resection and reconstruction of the defect is the best choice far the patient.3 Reconstruction of the anterior mandibular part has been considered to be necessary by majority of head and neck surgeons from the esthetic and functional point of view. Conside­rations about the lateral defect reconstruction differ. 1 Comparing results of perfarmed reconstruc­tion of the defect with those without it, better function has been shown in patients with pri­mary reconstruction of the mandibular defect with microvascular osteocutaneous free flap.4 The second metatarsal bone, the radius and the fibula have been used far the mandibular reconstruction, always together with a part of skin far a defect reconstruction in the oral cavity in our series of microvascular ostecuta­neous free flaps. Drawing a parellel among those tree afare- , mentioned flaps regarding the quality of the bone and skin, the length and vessel diameter of the pedicie, donor site complications and the possibility of two medica! teams working toge­ther, the fallowing can be conciuded: Fibular microvascular free flap provides the highest al. and the best quality in ali tree dimensions, longitudinally especially. This flap is the best far the mandibular bone defect reconstruction only5 while the skin is of poorer quality compa­red to the remaining two flaps described. Com­plications and morbidity of the donor site are less frequent than in the remaining two. Radia! microvascular osteocutaneous free flap has been frequently used in oromandibular 7 reconstruction.6• A bone of 10 to 12 cm is of low quality and insufficiently shaped in ali three dimension, being therefare bad far the mandibular recons­truction. The skin is of high quality, thin and suitable far reconstrucion of the soft tissue defects in the oral cavity. Donor site complications after the radia! flap transfer are the severest, being caracterized with frequent fractures of the radius. Of seven presented patients in our series in three of them developed a radia! fracture ( 43 % ) ; Soutar and Widdowson5 14 % ; Boorman et al.8 31 % and Urken1 23%. Metatarsal microvascular ostecutaneous free flap is one of the first that has been used far the oromandibular reconstruction (Rosen et al., 1979)9 providing the shortest bone (7 to 10 cm) of satisfying dimensions. The skin is of high quality, convenient far soft tissue defect reconstruction in the oral cavity. Donor site morbidity is significant and of long duration. Fifty percent of patients from our series developed gait disturbances. Pro­blems connected with this flap are greater than benefits. Ali the three vascular osteocutaneous free flaps observed, have been equally suitable re­garding the length and blood supply of the pedicled flap and the possibility of two medica! teams working at the same tirne. References l. Urken ML. Composite free flap in oromandibular reconstruction. Arch Otolaryngol Head Surg 1991; 117: 724-32. Oromandibu.Lar reconstru.ction with microvascular osteocu.taneou.s free [Lap 2. Juretic M, Car M, Zambelli M. The radia! free flap: our experience in solving donor site problems. J Cranio Maxillo Facial Su.rg 1992; 20: 184-6. 3. Vaughan E. The radia! forearm free flap in orofa­cial reconstruction: personal experience in 120 con­secutive cases. J Cranio Maxillo Facial Surg 1990; 18: 2-7. 4. Urken ML, Weinberg H, Viskery C, Buchbinder D, Lawson W, Biller F. Oromandibular reconstruc­tion using microvascular composite free flaps. Arch Otolaryngol Head Neck Su.rg 1991; 117: 733-44. 5. Hidalgo D. Fibula free flap: a new method of mandible reconstruction. Past Reconstr Surg 1989; 84: 71-9. 6. Soutar D, Widdowson WP. Immediate reconstruc­tion of the mandible using a vasculared segment of radius. Head Neck Surg 1986; 8: 232-46. 7. Swanson E, Bovd JB, Mankelow R. The radia! forearm flap: Reconstructive applicationes and do­nor site defects in 35 consecutive patiens. Plast Reconstr Surg 1990; 85: 258-66. 8. Boorman JG, Brown JA, Sykes PJ. Morbidity in the forearm flap donor arm. Br J Plast Surg 1982; 40: 207-12. 9. Rosen I, Bell M, Barron P, Zuker R, Manketelow R. Use of microvascular flaps including free osteo­cutaneous flaps in reconstruction after composite resection for radiation -recurrent oral carcinoma. Am J Surg 1979; 138: 544-9. Radio! Oncol 1994; 28: 194-9. Diagnosis and treatment of malignant mesothelioma of the peritoneum Erika Brencic,1 Marjeta Stanovnik,2 A. Višnar-Perovic1 1 Institute of Diagnostic and Interventional Radiology, Clinical Center, Ljubljana, 2 Institute of Oncology, Ljubljana, Slovenia Six patients with malignant mesothelioma of the peritoneum (MMP) diagnosed by US and CT between 1982 and 1992 are presented. MMP was suspected on the basis of diffuse changes in the peritoneum, omentum and mesenterium. The diagnosis was confirmed by cytological and histological examinations. The very suspicion of MMP based on US and CT alone, without the presence of typical symptoms, may shorten the time to definitive pathomorphological diagnosis. Ali patients were treated by combined chemotherapy (ChT), whereas four also underwent surgery and irradiation (RT). Four patients have died and two are alive with disease. A relatively prolonged survival was achieved only in two patients receiving multimodal therapy; this was probably influenced by the patients' youth, good performance status at the beginning of therapy and prognostically favourable MMP subtype. Key words: mesothelioma, peritoneal neoplasms Introduction Malignant mesothelioma of the peritoneum (MMP) is a rare primary malignant disease. The disease may affect the peritoneum, though its pleural invasion is more common. 1• 2 Men exposed to a contact with asbestos are affected in a greater percentage. It can be expected that the expanding development of asbestos industry will result in an increased number of new cases of this disease. The latent period from the exposure to asbestos and the onset of disease Correspondence to: Erika Brencic,· MD, PhD, Insti­tute of Diagnostic and Interventional Radiology, Cli­nical Center, Zaloška c. 7, 61105 Ljubljana, Slovenia. Fax: + 38 61-13-10-44. UDC: 616.381-006.32-07-08 is know to be very long. The mechanism of asbestos action upon the peritoneum has not been explained yet. 3 Symptoms of this disease show great diversi­ty, ranging from colic pains to loss of body weight. Clinical examination may reveal ascites with or without palpable tumor masses. The diagnosis of MMP is often established only after explorative laparotomy or on auto­psy. Classical radiological methods are insufficient as they can image different stages of changes in the intestinal mucosis, without actually being able to explain the organic cause of obstruction. The establishing of correct diagnosis is rendered very difficult as the disease closely resembles the clinical picture of abdominal carcinomatosis 5 and carcinoid involvement.4• Diagnosis and treatmenl of malignant mesothelioma of the peritoneum US and CT are noninvasive diagnostic met­hods able to present small or diffuse peritoneal, omental and mesenterial changes, with exclu­sion of a metastatic involvement. US-and CT­guided aspiration biopsies for cytological exami­nation help to provide fast and accurate diagno­ sis. 6, 7, s Systemic or intraperitoneal (IP) ChT in com­bination with surgery or radiotherapy (RT) resulted in a prolonged survival in a selected lO, 11 group of patiens.9• According to the expe­ 12 rieuces of other centers9 • longer survival can be attributed to the following factors: sex, early stage of disease, younger age, histological sub­type of MMP and good performance status at the beginning of treatment. Materials and methods In the period from 1982 to 1988, 51 patients with malignant mesothelioma were registered by the Cancer Registry of Slovenia at the Institute of Oncology in Ljubljana. 13 The success of treatment and diagnosis was reviewed in 6 patients with MMP treated during the years 1982-1992 at the Institute of Oncolo­gy. Table l. Basic data on the six studied patients. Pat. Age Asbestos Mode of biopsy No. Sex exposure and finding Site 1 32/M possible Biopsy on lapt. Peritoncum tubulopapillary MMP subtype 2 49/M yes Biopsy on laps. Peritoneum epitheloid MMP subtype 3 56/M no Aspir. biopsy of Peritoneum, the inguin. lgl pleura, lung, inguin. lgl 4 27/M no data Biopsy on lapt. Peritoneum multicentric inguin. lgl MMP subtype 5 56/M yes Aspir. biopsy Peritoneum of the asci tes 6 47/M ycs Aspir. biopsy Peritoneum of the ascites Abbreviations: lapt. -laparotomy; laps. -laparoscopy Ali patients were males in the mean age of 44 years. Exposure to asbestos was confirmed in 3 of 6 patients. In one patient such exposure was possible whereas in another one it was excluded. No data on possible exposure to asbestos were available for one patient (Table 1). In Pat. 1 and Pat. 4 the histologic diagnosis was confirmed by biopsy on Iaparotomy, and in two patients by aspiration biopsy of the ascites. Pat. 3 underwent aspiration biopsy of the inguinal lymph nodes, whereas Pat. 2 had the diagnosis confirmed by biopsy on laparo­scopy (Table 1). Epithelial subtype of MMP was established in Pat. 1 and Pat. 2. Multicystic subtype of MMP was histologically confirmed in Pat. 4. In the remaining three patients aspiration biopsy failed to identify the histologic subtype. The diagnosis of MMP was confirmed by autopsy in ali four deceased patients. In five patients the initial CT examination was carried out at the tirne of diagnosis, whe­reas Pat. 1 had CT performed only on the follow up after the initial therapy. CT examination was always performed with 5-sec. exposure tirne and 16 mm distance bet­ween individual sections through the entire abdominal cavity. Intestinal loops were imaged by means of Gastrografin, a contrast medium for oral application. For exclusion of metasta­ses, the results of investigations for the asses­sment of peritoneal, omental and mesenterial involvement, possible presence of ascites and changes in other organs were considered. Separate CT examinations of the thorax were not performed, though the pleura! space above the diaphragm was imaged in all patients. Peritoneal involvement was found in all cases; in Pat. 3 and Pat. 4 the disease was present in the inguinal lymph nodes, whereas in the for­mer patient pleural and pulmonary involvement was found as well (Table 1). Debulking surgery was performed in Pats 1, 2, 4 and 5. Two patients were not subjected to surgery, one because of pulmonary and pleural dissemination, and the other because of nume­rous peritoneal tumor infiltrations (Table 2). Brencic E et al. Table 2. Treatment sequence and outcome. Pat. No. Treatment sequence No. of surg. From dg to death Interval(mos) From compl. th to last follow-up Outcome 1 lapt (bx)iv.ChT > 4 90 10 dead RT> iv.Cht> lapt(ex) > ip.ChT > lapt > lapt laps(bx) > iv .ChT > RT 1 4 1 dead 3 iv.ChT o 10 7 dead 4 lapt(deb) > iv.ChT 1 15 alive with disease >RT>iv.ChT 5 iv.ChT> lapt(deb) 1 21 11 dead >iv.ChT>RT - 6 iv.ChT o 5 alive with disease Abbreviations: lapt -laparotomy; laps -laparoscopy; iv.ChT -intravenous chemotherapy; ip.ChT -intraperitoneal chemothe­rapy; RT -radiotherapy; bx -biopsy; deb -debulking surgery; ex -explorative surgery; > -followed by Table 3. No. of cycles, combination of drugs and irradiation. Pat. No. of cycles and drug. comb. Abdom. RT Fract. Duration No. iv.ChT ip.ChT TD-cGy cGy (days) 1 11/ADM, CTX, CDDP 1/ADM 7/ADM, VP16, CDDP CDDP 2.980 80/100 11/21 6/CDDP, MIT, IFO 2 2/MIT, 5-FU o 3.000 100 30 3 5/ADM, CTX, CDDP o o o o 4 6/ADM, CTX, CDDP o 3.000 300 10 S/MIT, C only pelvis 5 3/VLB 3/ADM, CTX, IFO o 3.450 150 23 6 2/MIT, CDDP, VCR o o o o Abbreviations: ADM -doxorubicin, CTX -cyclophosphamide, CDDP -cis-platin, VP16 -etoposide, MIT -mitomycin, 5-FU -fluorouracil, C -carboplatin, VLB -vinblastine, VCR -vincristine, IFO -ifosfamide Ali 6 patients were given a systemic chemo­therapy (ChT). Pat. 1 received a single intraper-. tioneal (i. p.) application of ChT which was ineffective (Table 3). Different combinations of cytostatics and dif­ferent numbers of cycles were used (Table 3). Four patients were also irradiated. Three of these received TD 2980-3450 cGy to the whole abdomen, whereas in Pat. 4 the irradiation field was restricted to pelvis alone (Table 3). Follow up included chest X-ray, US, CT of the abdomen and cytologic examination of the ascites. US-guided aspiration biopsy was used in order to evaluate possible progression of the disease. Results The initial CT examination revealed peritoneal involvement in 5 patients by imaging the thicke­ning and irregular contours of the peritoneum. Pat. 1 had the initial CT performed only on the first follow-up examination after therapy. The thickened peritoneum found on that occasion (Figure 1) persisted throughout the follow-up of 90-month lasting course of disease. When comparing the results of ali follow-up examina­tions, only the quantity of ascites was found to have varied. Tumor masses that appeared occa­sionally did not exceed 5 cm of size (Figure 2) and were located in different sites, most fre­ Diagnosis and treatment of malignant mesothelioma of the perito11eum Figure 2. CT image of a soft-tissue tumor (big arrow) situatecl between the intestinal loops ancl the abclomi­nal wall; thickened peritoncum (small arrow). quently between intestinal loops. Associated with further progression of the disease, these tumors obstructed the intestinal loops and con­sequently caused the patient's death. On the first examination in three patients tumors larger than 5 cm and the density of 20-30 HE were found. At that tirne, ascites was present in 5 patients, its density ranging bet­ween 10-20 HE (Figure 3). In five patients increased distance between the anterior abdo­minal wall and intestinal loops could be seen due to ascites and omental changes (Figure 4). Thickened mesenterium was found in ali pa­tients. In two of them this could be ascribed to the stellate mesenterial changes caused by the presence of small tumors and their consequen­tial obstruction of blood supply. None of the patients had any pleural outflow at the tirne of the first CT examination. Pat. 3 and Pat. 4 showed evidence of lymph node involvement (Table 1), whereas changes in the pleura and Jung of Pat. 3 appeared soon after the beginning of therapy. In Pat. 1 a combination of different treatment modalities (Table 3) resulted in a 90 month survival. The pr>tient died because of progres­sing disease and ileus. Pat. 5 died 21 months after the diagnosis, despite the combined thera­py. Only a short-lasting remission was achieved in 2 patients who survived 4 and 10 months respectively. Two patients are stili alive, one of them with palpable tumors in the peritoneum and inguinal lymph nodes. His disease, how­ever, shows tendency of stagnation, and the patient has been off the specific treatment for Brencic E et al. 15 months already. The other patient had been receiving ChT for 5 months, but the only thera­peutic effect achieved was a decrease of ascites (Table 3). Toxic side effects after ChT and RT were moderate. No life-threatening adverse reactions occurred during therapy. Discussion MMP can be successfully diagnosed by US and CT, when these are complemented with aspira­tion biopsy. The diagnosis or suspicion for MMP is based on the presence of ascites, and peritoneal, omental and mesenterial changes which can be imaged on CT. CT examination speeds up the diagnostic procedure and helps to provide the fina! diagnosis of MMP .. In some of our patients follow-up by means of CT was able to confirm the presence of disease (tumors and ascites) during therapy. In others, however, CT failed to evidence the disease, though microscopic peritoneal changes detectable only by aspiration biopsy might have been present. Treatment results of the presented patients with MMP are poor and in agreement with those reported in the literature: the duration of survival is 2, 12 and 18 months after diagno­ 3, s. 14 sis. Patients with well differentiated papillary MMP and cystic form of MMP were found to have a longer survival even without treatment. 14 Considering the small number of studied pa­tients, the combined therapy in Pat. 1 and Pat. 4 resulted in 33 and 90 month survival, respec­tively. Both patients had prognostically favoura­ble epithelial and multicentric MMP subtype. They were young and had a good performance status at the beginning of treatment. In both cases the combined treatment comprised debul­king surgery and RT. Pat. 1 received a single i. p. application of ChT, which could not be continued owing to ileus. The patient died 90 months after the beginning of treatment. Pat. 4 has been without a specific therapy for 15 months, and is alive with evidence of disease 33 months after diagnosis. At the beginning of treatment, Pat. 5 was over 40 years old, and had a residual tumor of unknown MMP subtype; he died 21 months after diagnosis. It is believed that the relatively longer survival of this patient could be attribu­ted to undiagnosed, possibly favourable MMP subtype. In two of six patients, short survival ( 4 and 10 months respectively) was due to their rapid course of disease. Combined therapy was inef­fective also because of unfavourable prognostic factors at the beginning of therapy, though one of them had the epitheloid MMP subtype. Pat. 6 has been only receiving ChT for 5 months now. It is interesting to note that one of the patients was not exposed to asbestos, and died with pleural and pulmonary involvement 10 months after diagnosis. Owing to unspecific clinical symptoms and late establishment of correct diagnosis, the pa­tients with MMP are generally admitted for treatment with highly advanced stages of the disease.3 Therefore, the treatment intent is of­ten limited to palliation. In their study, though it was carried out on a smaller number of patients, Lederman et al. reported that a longer survivaJ had been achie­ved by combined therapy. LO, 11 The survival of patients with combined radical therapy is longer than that of patients receiving palliative treat­ment only. Based on the correlation of our findings with the results of other studies, 14 we believe that MMP is possibly curable in patients with favourable prognostic factors. Considering that this is a rare disease, the number of patients in individual studies is gene­rally small. Though being rather low, the num­ber of patients with longer survival points out the need for multicentric studies to be carried out, so that the optimum treatment for MMP could be determined on a larger population of patients. Diagnosis and treatmenl of malignant mesolhelioma of the periloneum References 3rd l. Haskell CM. Cancer Trealment, Edition, W. B. Company 1990; 188: 300. 2. Suzuki Y. Pathology of Human Malignant Meso­thelioma. Seminars in Oncology 1981; 81: 268. 3. Plaus WJ. Peritoncal Mesothelioma. Arch Surg 1988; 123: 763. 4. Whitley NO, Brenner DE, Antman KH, Grant D, Aisner J: CT of Peritoneal Mesothelioma. Analysis of Eight Cases. AJR 1982; 138: 531. 5. Granke SD, Ellis JH, Richmond DB. CT Findings of Hipervascular Malignant Peritoneal Mesothe­lioma. Computerized Radio/ 1987; 11: 91. 6. Reuter K, Raptopoulos F, Krolikowski FJ, D'Orsi CJ, Graham S, Smith EH: Diagnosis of Peritoneal Mesothelioma. Computed Tomography, Sono­graphy and Fine-needle Apsorption Biopsy. AJR 1983; 140: 1189. 7. O'Neil JD, Ros PR, Storm BL, Buck JL, Wilkin­son EJ. Cystic Mesothelioma of the Peritoneum. Radiology 1989; 170: 333. 8. Pui-Li Y, Guico R, Parikh S, Chin S. Cystic Mesothelioma of the Retroperitoneum. J Ciin Ultrasound 1992; 20: 65. 9. Antman KH, Klegar KL, Pomfret EA, Osteen RT, Amato DA, Larson DA, Corson JM. Early Peritoneal Mesothelioma. A Treatable Malignan­cy. Lancet 1985; 2: 977. 10. Lederman GS, Recht A, Herman T, Osteen R, Corson J, Antman KH. Long-term Survival in Peritoneal Mesothelioma, The Role of Radiothe­rapy and Combined Modality Treatment. Cancer 1987; 59: 1882. 11. Lederman GS, Recht A, Herman T, Osteen R, Corson J, Antman KH: Combined Modality Treatment of Peritoneal Mesotheliomas. NCJ Mo­nogr 1988; 6: 321. 12. Antman KH, Shemin R, Ryan L, Klegar K, Osteen R, Herman T, Lederman G, Carson J. Malignant Mesothelioma. Prognostic Variables in a Registry of 180 Patients, the Dana-Farber Can­cer Institute and Brigham and Women's Hospital Experience over Two Decades, 1965-1985. J Ciin Oncol 1988; 6: 147. 13. Cancer Incidence in Slovenia 1988. Institute of Oncology, Ljubljana, Report No. 30, Ljubljana, 1992. 14. Antman KH, Pass HI, Recht A. Benign and Malignant Mesothelioma. Cancer: Principles and Praclise of Oncology. Third edition. De Vita V. T. Jr. et al., Ed.: Philadelphia, Lippincott 1989: 1399. Radio! Oncol 1994; 28: 200-4. Human papilloma viruses 16 and 18 in patients under 40 years of age with operable squamous cancer of the uterine cervix Marjetka Uršic-Vršcaj,1 Jurij Lindtner,1 Jožica Marin2 12 Institute of Oncology, Institute of Microbiology, Ljubljana, Slovenia '. Numerous investigations support the belief that human papilloma viruses (HPV) play an important role in the etiology of cervical cancer. Our study carried out in 31 patients with operable squamous cervical carcinoma (SCC), who were under 40 years of age, was aimed to investigate the incidence of HPV 16 and 18 infection in this group of patients, their sexual behavior as well as the efficacy of Slovene gynecological service in cervical cancer detection. HPV 16 was found in 67% and HPV 18 in 22 % of our patients, which is consistent with the data reported by other authors. Key words: human papilloma viruses cervix neoplasms-etiology Introduction In the majority of western countries the inci­dence as well as the mortality of SCC have been gradually decreasing since 1950, as a result of their carefully planned and systematically practised strategy for early detection of this disease. On the other hand, the facts that cervical cancer related deaths are the most frequent in women urider 40 years of age, and that an increasing trend in SCC incidence has been reported in some areas in that particular 2 age group, should not be ignored. 1• A prere­qusite for a successful mass screening for pre­cancerous conditions of the uterine cervix and non-invasive cancer is certainly the simple and painless method of cervical smear taking at the · tirne of gynecologica! checkup. Papanicolaou Correspondence to: M. Uršic-Vršcaj, MD, MSc, Insti­tute of Oncology, Zaloška 2, 61105 Ljubljana, Slove­nia. UDC: 618.146-006.6-022:616.988.15 test, or shortly "Pap test" (PT) was introduced in 1941 by Papanicolaou and Traut, and it has becorne a synonym for a cornplete gynecological examination. Though the value of PT is in­disputable, some drawback of this diagnostic method nevertheless need to be pointed out. The most re!evant is certainly the fact that cytomorphology is unable to foretell which of the seemingly indistinguishable (identical) pre­cancerous changes will sooner or later turn into intraepithelial or invasive carcinoma. The changes caused on cells by papilloma viruses were described a!ready in 1933. Due to the Jack of suitable cu!tures (growth media) and some serological tests, it was only after 1970 that a possible correlation between HPV and cervica! cancer became apparent on the basis of severa! experimental, clinical and epidemio­logical studies. Advances in molecular biology, particularly the discovery of polymerase re­action (PCR) which is the most sensitive me­thod of HPV detection (as compared to others such as in situ hybridization and dot blot hybri­ Human papilloma viruses 16 and 18 in patients with operable squamous cancer of the uterine cervix 201 dization), resulted in the isolation of over 60 different HPV genotypes. The types 6 and 11 are associated with benign changes in the ute­rine cervix. Their presence most probably does not represent an increased risk of cervical can­cer. HPVs 16, 18, 31 and 33 are, on the other hand, considered to be oncogenic HPV types, as they can be frequently seen in intraepithelial cervical dysplasias (CIN II*), in severe dyspla­sias or in noninvasive squamous carcinoma of the uterine cervix (CIN III) and invasive SCC. According to some data, HPV 16 and 18 can be found in 1.5 % of healtly women, in 20-40 % of patients with squamous intraepithelial chan­ges (CIN I), in 60-80 % of patients with changes described as CIN II and III, as well as in 3 80-90 % of patients with SCC. 1· The present report was aimed to explain the role of certain suspected risk factors in the sexual behavior of patients, believed to be associated with the appearance of SCC. We also wanted to establish the number of gyneco­logical checkups performed within two years before diagnosis, as well as the number of cytological smears and cytological findings in the same period, and to determine the percent­age of patients with HPV 16 and 18. Patients and methods The study included 31 patients younger than 40 years, who were treated for operable squamous carcinoma of the uterine cervix at the Depart­ment of Gynecology of the University Clinical Center, and at the Institute of Oncology in Ljubljana, in the period from February 1990 to February 1992. The data were collectec by means of a que­stionnaire comprising general as well as specific * It seems that the international classification of in­traepithelial cervical neoplasms (CIN), which was ac­cepted in 1973, will be replaced by a new classification from Bethesda, where CIN I stands for "low grade" squamous intraepithelial lesion, whereas CIN II and III denote "high grade" squamous intraepithelial le­sion; this classification system is based on the degree of probability to develop cancer. questions related to the patient's lite syle, her gynecological and reproductive history and se­xual behavior (age at first sexual intercourse, the number of partners in the last two years), and the type and duration of contraception used. We also collected the data on patients' imminent gynecological problems just before diagnosis and on the number of cytological smears taken during the last two years before diagnosis. Each patient had cervical smear for the deter­mination of HPV 16 and 18 taken on gynecolo­gical checkup. Tests for the presence of HPV 16 and 18 ware done at the institute of Micro­biology in Ljubljana. The serum levels of vita­min A and beta-carotene were also determined in each patient in order to establish possible correlation between a decrease in these values and the appearance of SCC metastases. The patients were followed up for 12 to 36 months after the diagnosis. Sample processing Smear samples were immersed in 2 ml of phos­phate buffer saline (PBS) at 7.4 pH, and imme­diately taken to the laboratory for further pro­cessing. After the PBS immersed smears are well shaken on a vortex, the smears alone are removed while PBS with cells in centrifuged at 2000 rpm for 10 min. Using glass slides, two smears from the celi sediment are made for HPV-16 and HPV-18 determination. The slides are then air-dried and fixed in cold acetone for 7-10 min. Thus prepared samples can be stored at -20 °C for a longer period of tiine till hybri­dization, or the hybridization procedure can be started immediately. Hybridization in situ by means of biotinilated DNA probes Control slides for negative and positive check were included in eash test. The samples were first immersed in 0.3 % in methanol for H202 15-30 min. in order to stop the activity of endogenous peroxydase; 3-5 ul of biotinilated Uršic-Vršcaj M e/ al. DNA probe were added to the smears, which were after wards covered with slips and heated at 100-105 °C on a metal plate tor 10 min. with the aim to unbind the double-stranded target DNA. The procedure is followed by 2-hr incubation in a humid chamber at 37 °C (the incubation can be continued overnight). Afterwards, the slides are held vertically and rinsed in 2 X SSC with 0.1 % SDS addes until the slips fall off. The rinsing in repeated severa! times, finally with PBS. Each smear is covered with 10 ut of strepta­vidin-peroxydase complex and left to incubate tor 30 min. at 37 ° C betore being rinsed with PBS three times. To obtain staining reaction, a drop of diamy­nobenzidine with addition of H202 substrate is put onto each smear. Thus prepared samples are incubated for 15 min. in dark at a room temperature. The reaction is stopped by immersing the slides into distilled water. After contrast stai­ning with Mayer's hematoxilin tor 1-2 min, the samples weree rinsed in running water. The slides were then dehydrated in growing concentrations of ethano.l (to 100%), and im­ mersed in xylol; after adding a drop of PBS and glycerine (1: 10), the slides were covered with cover slips. Microscopic examination is done by means of a light microscope. We used the reagents produced by Epignost company. Positive reaction is evident from brown­ stained celi nuclei (Figure 1, image 30). There is no brown precipitate in the nuclei seen in negative reaction (Figure 2, image 28). Results The studied patients were younger than 40 years, their mean age being 33 years. The youngest patients was 20 years old. As to education, 40 % of our patients had primary and vocational school; 55 % of their partners had equal educatioon (the same leve! of education). Most patients did not suffer from defficiency of vitamin A in their tood either during child­hood or adolescence period. Over a half of the patients (58 % ) were smokers; they smoked 20 cigarettes daily from 19 years on average. The data on familial gynecological cancer burden were avialable for 3 patients only. Most patients were married (80 % ) , two were divorced. Their mean age at marriage was 23 years. Mean age at menarche was 13 years, and at the first sexual intercourse 17 years. In the last two years betore diagnosis, ali patients claimed having sexual relation with one partner only. Neither the data on urogenital diseases of part­ners nor on their past relationships SCC pa­tients were available. Two patients were nulliparous, whereas the rest gave birth twice at an average age of 21 years; 65 % of patients had abortions, the first one at an average age of 21 years. Only one patient had a spontaneous abortion. 65 % of patients were using hormona( contra­ceptives for 60 months on average, starting at 24 years of age. A half of the patients got IUD protection at an age of 26 years and were using if for 70 months on average. One third of the patients (32 % ) were not gynecologically exami­ned within the last two years before the diagno­sis, though a majority of them (77 % ) claimed that they attended regular annual checkups. In the last two years before the diagnosis, 73 % of the patients underwent one or two, and the rest more than two gynecological examinations. Before the onset of disease, 45 % of the patients were free of any gynecological comp­laints while 35 % of them presented with recur­rent vaginitis. The main symptoms before diagnosis were bleeding (55 % ), pain (50 % ) and vagini tis (23 % ) . Four patients with SCC were pregnant at the time of diagnosis. 6 % of patients had no gynecological complaints. Cytological smear (P AP) was not taken with­in two years betore diagnosis in 35 % of pa­tients, while 26 % had one and 32 % two smears taken. In almost a half of the patients with cytologic smear taken, this was done within the Human papilloma viruses 16 and 18 in patienls 1vilh operable squamous cancer of the uterine cervix 203 year before diagnosis; 35 % of the smears were classified as negative. The disease was diagnosed by biopsy in 71 % of the 31 patients, whereas the remaining ones underwent conization. On admission, 90 % of patients had Stage I, 81 % of these stage lb of the disease. 81 % of patients were treated by surgery, and two received preoperative Ra applications. One fifth of the patients were also given postopera­tive radiotherapy. Treatment-related complications Minor urological complications were noted in 4 patients; two of these were treated by surgery and irradiation. Three patients presented with recurrence (2 local, 1 distant), ali of them within 6 months after primary therapy. Two patients died within the first year after diagnosis. Normal vitamin A values were established in 84 % , and normal .-caroten in 44 % of patients. The presence of HPV-16 was confirmed in 67 % , and of HPV-18 in 22 % of patients. Further, HPV-16 was found in 2 of three pa­tients with uncontrollable disease, whereas HPV-18 presenmce was not established in any of those patients. Discussion According to the data of the Cancer Registry of Slovenia, in 1986 cervical cancer was stili the sixth most frequent cancer in Slovene female population. From 1977 on, the crude incidence (15/100,000) has remained basically unchanged. A moderate increase (5.3 % ) can be observed only among women of 60-64 year age group. Also the relevant mortality rates (5.6/100,000) in the past few decades have been virtually the same. In 1960 a systematic screening for cervical cancer (CC) was started throughout Slovania. However, according to the data from 1966, such organized screening for precancerous changes and intraepithelial cervical cancer was available in some of the Slovene communes only. One of the criteria for the evaluation of the effectiveness of cervical cancer detection is the rate of established intraepithelial vs. inva­sive cancers; for Slovenia, this rate is 1.2. The small number of patients with intraepithelial CC and the high number or those with invasive CC, as well as concequentially high mortality due to this type of cancer call for a systematic screening for CC, supported by additional inve­stigations, particularly in the litoral communes of Izola, Koper and Piran, and in Maribor. We presume that the poor results of screening for precancerous and early forms of CC in these regions are attributable to the so-far unexplai­ned risk factors such as HPV, as well as to the specific life style believed to be associated with the etiology of CC. Numerous studies have long been supporting the belief that the risk of SCC is in correlation with woman's sexual behavior (e.g. the first sexual relation before 18 yrs of age, numerous sexual partners), as well as with education leve!, marriage before the age of 18 yrs, a higher number of births and abortions, smo­king, less frequent use of mechanical contracep­tives, and oral contraceptive use.4· 5 However, considering the results of multivariate analyses, any conclusion based solely on the presumed association of CC morbidity and sexual beha­vior is not convincing.4-6 Our data are consi­stent with the reported as to the age at first sexual relation, education, smoking, number of abortions and the use of contraceptives. The fact that one third of patients fail to undergo a gynecological examination within the last two years before diagnosis points at the deficient organization of our gynecological service and monitoring of temale population at risk, parti­cularly since two thirds of cytological smears are confirmed as pathologic.7 According to the results of numerous studies, the two most relevant risk factors associated with the etiology of SCC are 1) the degree of dysplasia of the squamous epithelium of the uterine cervix, and 2) the presence of HPV infection. Apart from their relevance for diagnosis, Uršic-Vršcaj M et a/. HPVs -particularly HPY-18 -are also consi­dered increasingly important for their progno­stic value. It seems that HPV-JS is more viru­lent than other oncogenic HPVs, and that the fast-growing CC are presumably associated with 9 the presence of HPY-18.8­ It has been found that in adenocarcinoma HPV-18 is present in 30-60 % whereas HPV-16 is found in only 20 % . In SCC this proportion 15 is just the opposite.11­ Endocervical smear taking, which should be an integral part of every routine gynecological examination, together with testing for HPY-16/ 18 infection, might -at least to some extent ­help to reduce the incidence of SCC. According to our data, the presence of HPY-16 was esta­blished much more frequently than the presence of HPY-18. Contrary to our expectations, HPY-18 could not be found in patients with recurrent disease, which might be attributable to the lesser relia­bility of the methods used. Perhaps, this is also why the results are somewhat disappointing. A new study using more advanced methods might help to resolve severa! interesting qu­estions on possible association between HPY infection and gynecological neoplasms. Ref'erences 1. Helmerhorst TJM, Kenemans P. Walboomers JMM, Meijer CJLM, Lammes FB. Is HPV screen­ing beneficial in the fight against cancer of the cervix uteri? ECC Newslett 1992; 1: 15-6. 2. Jarrell, MA, Heintz N, Howard Pet al. Squamous celi carcionoma of the cervix: HPV 16 and DNA ploicly as predictors of survival. Gynecol Oncol 1992; 46: 361-6. 3. Ambros RA, Kurman RJ. Current concepts in the relationship of human papillomavirus infection to the pathogenesis and classification of prccancerous squamous lesions of the uterine cervix. Semin Diagn Pathol 1990; 7: 158-72. 4. Lorincz AT, Reid R. Association of human papil­lomavirus with gynecologic cancer. Curr Opin Oncol 1989; 1: 123-32. 5. Nuovo GJ, Blanco JS, Lepzig S, Smith D. Human papillomavirus detection in cervical lesions non­diagnostic for cervical intraepithelial neoplasia: corrclation with Papanicolau smear. colposcopy, ancl occurrencc of cervical intraepithelial neopla­sia. Obstet Gynecol 1990; 75: !006-ll. 6. Pasetto N, Sesti F, cle San tis L, Piccione E, Novclli G, Dallapiccola B. The prevalencc of HPVJ6 DNA in normal and pathological cervical scrapes using the polymerase chain reaction. Cy­necol Oncol 1992; 46: 33-6. 7. Pompe Kirn V, Kovacic J, Primic Žakelj M. Epiclemiological evaluation of cervical cancer scrccning in Slovenia up to 1986. Eur 1 Gynecol Oncol 1992; 13: 75-82. 8. Kjaer SK. Engholm G. Teisen C et al. Risk factors for cervical human papillomavirus ancl herpes simplex virus infections in Greenlancl and Denmark: a population-based stucly. Am 1 Epide­miol 1990; 131: 669-82. 9. Murthy NS, Sehgal A, Satyanarayana L ct al. Risk factors relatecl to biological behaviour of precancerous lesions of the uterine ccrvix. Br J Cancer 1990; 61: 732-6. 10. Jones CJ. Brinton LA, Ham man RF et al. Risk factors for in situ cervical cancer: results from a case-control stucly. Cancer Res 1990; 50: 3657-62. 1 l. Burnett AF, Barnes WA, Johnson JC et al. Prog­nostic significance of polymerase chain reaction detectecl human papillomavirus of tumors ancl lymph nocles in surgically treatecl stage 1B cervical cancer. Cynecol Oncol 1992; 47: 343-7. 12. Horcling U, Stubbe Teglbjaerg C, Yisfelclt J, Bock JE. Human papillomavirus types 16 ancl 18 in adenocarcinoma of the uterine cervix. Gynecol Oncol 1992; 46: 313-6. 13. Macri CI, Cook NS, Walker JL, Berman M, Patton T.J, Wilczynski SP. Analysis of fine-neeclle aspirates for HPV by PCR may be useful in cliagnosis of metastatic gynecologic malignancies. Gynecol Oncol 1992; 46: 372-6. 14. Manclelblatt J, Richart R, Thomas L et al. Is human papillomavirus associatecl with cervical neoplasia in the elclerly? Gynecol Oncol 1992; 46: 6-12. 15. Palmer L, S Falkow. Selection of DNA probes for use in the cliagnosis of infections clisease. In: Kinsbury DT. S Falkow ecls. Rapid detection and identification of infectious agents, New York, Aca­clemic Press, !ne., 1985: 211-8. Radio/ Oncol 1994; 28: 205-8. Malignant Iymphoma mimicking metastatic adenocarcinoma Rastko Golouh and Andreja Zidar Institute of Oncology, Ljubljana, Slovenia We report a case of malignant lymphoma of the inguinal lymph node exhibiting gland-like structures and abundant jibrillary matrix, mimicking cytologically ancl histologically a metastatic aclenocarcino­ma. The only clue to the possible lymphomatous nature of the lesion was immun.ohistochemical study proving that this represented a B-cell non-Hodgkin's lymphoma, staining positively for leulwcyte common antigen, L26(CD20), lgG ancl kappa light chain, supported by ultrastructural jinclings of jilifonn cytoplasmatic processes on the surface of tumor cells. We conclude that the possibility of malignant lymphoma should not be disregarded even when a tumor shows glancl-like structures or cohesive growth pattern. Key words: lymphoma, non--Hodgkin's; adenocarcinoma, diagnostic pitfall Jntroduction An unexpected rnalignant process in the lymph nodes, especially in instances where microscopic changes are not sufficiently informative to de­cide whether the malignant cells show epithe­lial, mesenchymal or lymphoid phenotype, is a frequent problem facing surgical pathologist. The presence of glandular formations in meta­static tumors is strongly suggestive of the diag­nosis of metastatic adenocarcinoma. When ro­sette-like formations and abundant fibrillary matrix in poorly differentiated tumors are domi­nant, the diagnosis of neural tumors such as neuroblastoma or ganglioneuroblastoma are fa- Correspondence to: Rastko Golouh, MD, PhD, De­partment of Pathology, Institute of Oncology, Zaloška 2, 61115 Ljubljana, Slovenia. Tei: 386 61 1322 099, Fax: 386 611314180 vored. In this report we describe a unique case of a malignant lymphoma with gland-like struc­tures and abundant fibrillary rnatrix. Case report A 63-year-old female was observing a slowly growing lump in her left groin for 11 months. The swelling was interpreted by a surgeon as a hernia. Due to the acute pyelonephritis and transient renal insufficiency, the patient was admitted to a general hospital, where an aspira­tion biopsy of the inguinal tumor was performed and interpreted as a metastatic process of un­known origin. After admission to the Institute of Oncology, Ljubljana, an additional, 5.5 cm infiltrate of the left retroperitoneum was disclo­sed by laparoscopy. An excisional biopsy of a UDC: 616.428-006.442-079:616-006.66 left inguinal lymph node was performed. Golouh R and Zidar A Materials and methods Formalin and methacarn-fixed, paraffin embed­ded tissue sections were stained with hematoxy­lin and eosin, Giemsa, periodic acid Shiff and Kreyberg. Immunohistochemical staining was carried out on paraffin-embedded sections using the avidin-biotin-peroxidase complex technique with antibodies to keratin wide spectrum, vi­mentin, alpha-smooth muscle actin, S-100 pro­tein, leukocyte common antigen(LCA), T-mar­kers CD3, CD43, CD45RO, B-markers CD 20, CD22, MB2, Ig, kappa and lambda light chains, and activation marker CD30. The immunohi­stochemical staining was done with appropriate positive controls. For electron microscopic analysis, wet tissue fixed in 10 % neutral formalin was used. It was washed in phosphate buffer at Ph 7 .2, postfixed in buffered osmium tetroxide, and embedded in Epon LX-112. Thin sections were stained with uranyl acetate and lead citrate and exami­ned with an Opton 9 electron microscope. Results The resected tissue was a solitary, enlarged lymph node, measuring 4.5 x 4.0 x 3.0 cm. On the cut surface, the tissue was homogenous, pink, partially nodular. Necrosis was not evi­dent. Histologically, most of the lymphoid tissue was replaced by tumor cells forming cords, nests, severa] layers thick, with some solid areas and gland-like structures within the my­xoid stroma (Figure 1). The residual small germinal centers were surrounded by neoplastic cells, with their mantles often intiltrated. In some areas tumor cells were dissociated in between prominent capillaries. The tumor cells were round to oval, with eosinophilic or clear cytoplasrn. The nuclei were irregular, pleomor­phic, sometimes multilobated, with one to seve­ra! distinct nucleoli. In the cells of gland-like structures, the nuclei were situated peripheral­ly. The overall impression of the tumor resern­bled that of a metastatic, poorly differentiated adenocarcinoma with poorly developed myxoid stroma. However, stains for rnucin and keratin were negative. In contrast, the tumor cells showed definite membrane positivity for LCA (Figure 2) and CD20 (Figure 3). The cells also showed monotypic staining pattern for IgG with a definite kappa ligh chain excess, thus confirming their B lineage. Staining for CD 22 and MB2 was negative. The fibrillar matrix, expressed mostly within gland-like spaces, also stained strongly with LCA and CD20. T-Cell Figure 2. Clusters of tumor cells show membrane staining for leukocyte common antigen (CD 45 RB). Deeply stained central fibrillary .matrix aclditionally supports the wrong impression of glancl-like forma­tions. Malig11a111 lymphoma mimicking metastatic adenocarcinoma Figure 3. Tumor cells clemonstrating strong reactivity for B-cell marker L26 (CD 20). markers, actin, vimentin, S-100 protein ancl CD30 were ali negative. Thus, the immunohi­stochemical stuclies clearly showecl that the ini­tial impression of metastatic carcinoma hacl been incorrect, and proved the condition to be a large celi non-Hodgkin's malignant lymphoma of B-cell lineage. Ultrastructurally, the large lymphoid tumor cells displayed long, interdigitating cytoplasmic processes (Figure 4). These thin, filiform, bran­ching projections filled intercellular spaces, but also a solitary intracytoplasmic lumen filled with the same type of projections was found within a lymphoma celi. lnterce!lular junctions were absent. Follow-up The patient was treated by chemotherapy accor­ding to CHOP regimen, followed by regional radiotherapy (TD 2100 cGy). A complete re­mission was achieved. The patient is alive and well 9 months after the diagnosis. Discussion Malignant non-Hodgkin's lymphomas can occa­sionally exibit unusual histological patterns, such as sinusoidal growth in anaplastic large celi lymphoma (ALCL), CD30 positive, resem­bling metastatic carcinoma,1 spindle cells with Figure 4. Lymphoicl celi characterizecl by rouncl nu­cleus, fcw organelles ancl profuse intercligitating villo­poclial projections along the celi surface (x 5000). storifonn pattern similar to that seen in sarcoma or malignant melanoma,2 myxoid stromal chan­ges and cord like cellular arrangement not unlike that in myxoid chondrosarcoma3 or even signet celi differentiation simulating metastatic mucoid celi carcinoma.4 The gland-like structures with solid areas in a myxoid, vascularized stroma exhibited in this case were cytologically and histologically thought to be a poorly differentiated carcinoma metastatic to the lymph node, but negative stainings for mucins and cytokeratins rulecl out this possibility. The immunological studies provecl fruitful in demonstrating the lymphoid nature of this neo­plasm with definite membrane positivity for LCA and L26 (CD20) with IgG and kappa light chain clonality in the tumor cells. Adenocarcinoma-like change is a previously unrecognizecl pattern of malignant lymphoma. It is well known, however, that ALCL, CD 30 positive, characterized sometimes with varying degrees of sinusoidal and subcapsular infiltra­tion by large bizarre neoplastic cells might simulate other neoplasms, such as metastatic carcinoma,5 but adenocarcinornatous pattern in such cases has not been observed so far. The presence of an abundant extracellular rnucoicl rnatrix has not been considered to sup­ Golouh R and Zidar A portive in the diagnosis of lymphoma until the reports by Chan2 and Tse.3 They described a case of anaplastic large cell Ki-1 lymphoma with myxoid matrix showing unusual sarcoma­toid appereance and a case of B-cell malignant lymphoma in the soft tissue exhibiting promi­nent myxoid stromal changes. These authors claim that lymphoma tumor cells can elicit an exuberant myxoid change, probably by stimula­ting stromal cells. Contrary to their case of sarcomatoid lymphoma, where tumor cells were situated predominantly around the blood ves­sels, in the present case well defined perivascu­lar cuffs were absent. Groups of tumor cells were situated randomly without any evidence of angiotropism lacking appereance that would suggest the diagnosis of lymphoma. Histologically, the cytoplasm of the tumor cells merged into an abundant fibrillary matrix filling the central parts of gland-like and pseudo-rosette-Jike structures, but which was absent outside them. Similarly to the tumor cells, the fibrillary matrix stained with LCA and B-cell marker. Immunohistochemically and ultrastructurally, this case represents a type of filiform or anemone B-cell lymphoma which is characterized by multiple cytoplasmic project­ions on the celi surface.6 It is interesting that , in the current case, the cytoplasmic processes of the lymphoma cells were present almost exclusively in the center of celi groups thus forming the condensed eosinophilic fibrillary matrix which, seen on conventional histologic sections, was partially responsible for diagnosti­cally misleading organoid histological picture. As most of the matrix was made of cell mem­brane material, it readilly stained with mem­brane leukocyte markers. Given the wide range of histological appea­rances that malignant non-Hodgkin's lymphoma can assume, it is important and of clinical relevance not to exclude malignant lymphoma from differential diagnostic consideration even when the tumor shows gland-like or rosette-like structures or an apparently cohesive growth pattern. References l. Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pal lesen G, Gatter K, Fali ni B, Delsol G, Lemke H, Schwartig R, Lennert K. The expres­sion of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. 8/ood 1985; 6: 848-58. 2. Chan JKC, Buchanan R, Fletcher CDM. Sarcoma­toid variant of anaplastic large celi Ki-1 lymphoma. Report of a case. Am J Surg Pathol 1990; 14: 983-8. 3. Tse CCH, Chan JKC, Yuen RWS, NG CS. Malig­nant lymphoma with myxoid stroma: a new pattern in need of recognition. Histopathology 1991; 18: 31-5. 4. Kirn H, Dorfman RF, Rappaport H. Signet ring celi lymphoma. A rare morphologic and functional expression of nodular (follicular) lymphoma. Am J Surg Pathol 1978; 2: 119-32. 5. Penny RJ, Blaustein JC, Longtine JA, Pinkus GS. Ki-1-positive large celi lymphomas, a heterogenous group of neoplasms. Morphologic, immunopheno­typic, genotypic, and clinical features of 24 cases. Cancer 1991; 68: 362-73. 6. Bernier V, Azar HA. Filiform large-cell lympho­mas. An ultrastructural and immunohistochemical study. Am J Surg Pathol 1987; 11: 387-96. Radio/ Oncol 1994; 28: 209-20. Physical parameters for patient .ose reduction with X-ray filtration in diagnostic radiology L. John Schreiner, Noel Blais, J.-P. Bissonnette and Ervin B. Podgoršak Department of Oncology (Radiation Oncology) and Medica! Physics Unit, McGill University, Canada Although radiographic techniques have been established for clinical diagnostic studies, research continues in the reduction of patient dose through various technical modifications. However, dose savings from the adoption of different techniques are often reported using a variety of exposure or dose parameters. In this paper the evaluation of patient dose reduction in terms of surface doses and integral doses is analyzed. The review is performed using a specific example of dose reduction with various x-ray filter materials in order to illustrate the limitations of the various parameters for assessing risk reduction. The x-ray techniques required for each filter material to give a similar radiographic quality as the standard technique are established. The surface dose reductions, integral dose reductions, tube loading increases relative to the standard techniques are reported for the beams filtered with different materials. To clarify the differences between surface dose and integral dose savings, the integral doses are determined from depth dose data. An analysis of the relationship of effective dose equivalents to surface doses and integral doses indicates that the use of integral dose ratios more accurately specifies the risk reduction to the patient. Key words: radiation protection; patient dose; x-ray filters Introduction The aim of diagnostic radiology is to make an accurate diagnosis with the lowest possible ra­diation risk to the patient. Whereas standard radiographic techniques have been established over the years to achieve this goal, research to reduce the patient dose without compromising image quality continues. The effects of x-ray beam filtration on patient dose have been inve- Correspondence to: L. John Schreiner PhD, Depart­ment of Oncology and Medica! Physics Unit, McGill University, 1650 avenue , Bc, .; . ti>. .H 'l!i C CI) . . o o o._, t:. "iii .. H (1) _g_ > C q o (.) .01 I 2 3 4 5 6 7 HVL ( mm AI) 3 o b) H t:.. q 1 2. ;P. o lfj (1) MS. . ... lfj (1) o E: A. "O t:. o..._ uw "O :I: (1) -l. ! t:. .!::! H _g (1) I: E o o 1 2 3 4 5 6 7 HVL ( mm AI) Figure 4. The vanat,on of the relationship of the effective dose equiv.nt H E to the integral dose L, mean absorbed dose D, and surface dose Ds with the HVL of the radiographic technique for PA chest radiography. The data are taken from rneasurernents and calculations reported by Alm Carlsson and Carls­son (•) Shrimpton et al. (!-.), and Huda et al. (¦, D). These data are presented since they cover a range of HVLs similar to that covered in the present study. a) The conversion constants for determining H Es frorn rnean absorbecl dose and surface dose rneasurements. b) The same clata as above normalized to 1.0 at a HVL of 2.0mm of aluminum. This plot shows the relative change in the conversion factors as the HVL of the radiographic technique is increased. The solid line at a norrnalized conversion factor of 1.0 indicates the behaviour expected for a conversion factor which is independent of HVL. w in which HVLs of x-ray beams filtered by different materials may change considerably, the relative surface dose reduction is not a true 10c-...--.---,-.-r-.-.-.-.-.-, (1) lfj a) H E o "O I: ..._ ¦ ¦ ¦ Physical parameters for patient dose reductio11 with X-my filtra/ion in diagnostic radiology 2l9 indication of the effective dose equivalent since the conversion factor H d Ds may not be con­stant. Rather, the integral dose should be used for the risk reduction evaluation since the con­version factor H dL rernains essentially constant with changing HVL. With the results reported earlier, it is apparent that the risk reduction achieved by the use of novel x-ray filtration schemes is exaggerated by 10 to 45 per cent, if only surface dose or entrance exposure reduc­ tions are quoted. One further point can be made. The results for the samariu111 filter confirm a caveat31 often overlooked in filter discussions. As the experi­ments progressed the pararneters measured e111­pirically and determined by the cornputer calcu­lations no longer agreed. The e111pirical results for the dose reductions began to be less than those predicted by calculations. Yisual exarnina­tion of the 0.1111111 sarnariu111 foil used in the experirnents indicated that the foil had cracked. Therefore, the use of thin foils for practical x-ray filtration has an additional quality assur­ance aspect which 111ust be considered in the choice of optimal filtration. Conclusions While the measure of the dose reduction achiev­ed with rnodifications of diagnostic radiographic techniques (for exa111ple, by the use of different x-ray filters) is obviously critical in evaluating changes in patient risk, to date no standard dose parameter has been adopted for reporting the risk reduction. In this paper an evaluation of the physical para111eters used to describe the risk reduction resulting from the use of a variety of x-ray filter materials is presented. Yarious physical para111eters for the x-ray beams filtered by different 111aterials have been established. The radiographic techniques with the various filters were 111odified by increasing the tube kYp to equalize irnage quality to that obtained with the standard techniques. The integral dose reductions relative to the standard techniques achieved with the different filters are significan­tly less dra111atic than the reductions seen in surface dose. Further111ore, in ali cases the x-ray bea111s filtered by the new filter materials had HYLs thicker than beams filtered by the standard aluminurn. An analysis of previously reported data indicates that the conversion fac­tors for integral dose to effective dose equiva­lent, the parameter of choice in evaluating patient risk, are essentially independent of x-ray bearn quality (i.e., HYL). However, the factors for converting surface dose to effective dose equivalent increase dramatically as the HYL increases. This analysis clearly indicates that integral dose ratios more accurately specify the reduction in the patient radiation risk attained with different radiographic techniques. Descrip­tions of risk reduction based on surface doses or entrance exposures considerably overesti­111ate the benefit to the patient. Acknowledgements The authors would like to thank Ms. Marina Pia for her assitance with the TLD 111easure­rnents. References J. Yamaguchi C, Yamamoto T, Terada H, Akisada M. Effect of tungsten absorption edge filter on diagnostic x-ray spectra image quality and absor­bed dose to the patient, Phys Med Biol 1983; 28: 223-32 . 2. Burgess AE. Physical measurements of heavy metal filter performance. Med Phys 1985; 12: 3. Koedooder K, Venema HW. Filter materials for dose reduction in screen-film radiography. Phys Med Biol 1986; 31: 585-600. 4. Jennings RJ. A method for comparing beam-hard­ 225-8. ening filter materials for diagnostic radiology. Med Phys 1988; 15: 588-99. 5. Kohn ML, Gooch A W, Keller WS. Filters for radiation reduction: a comparison. Radiology 1988; 167: 255-7 . 6. Wesenberg RL, Amundson GM, Mueller DL, Coupland SG. Ultra-low dose routine pediatric racliography utilizing a rare-earth filter. J Can Assoc Radio! 1987; 38: 158-64. 7. Homer K, Lawinski CP, Smith NJO. Erbium filtration for dose reduction in dental racliology. Brit J Radio/ 1988; 61: 609-12. Schreiner LJ et al. 8. Nagel HD. Comparison of performance characte­ristics of conventional and K-edge filters in general diagnostic radiology. Phys Med Biol 1989; 34: 1269-87. 9. Thierens H, Kunnen M, Van der Plaetsen A and Segaert O. Evaluation of the use of niobium filter for patient